
Class 

Book 



COPYRIGHT DEPOSIT 



AN INTRODUCTION 

TO 

CHEMICAL PHARMACOLOGY 



McGUIGAN 



AN INTRODUCTION 

TO 

Chemical Pharmacology 



Pharmacodynamics in Relation 
to Chemistry 



BY 



HUGH McGUIGAN, Ph.D., M.D. 

PROFESSOR OF PHARMACOLOGY, UNIVERSITY OF ILLINOIS. 
COLLEGE OF MEDICINE 



PHILADELPHIA 
P. BLAKISTON'S SON & CO 

1012 WALNUT STREET 






0$ 



Copyright, 1921, by P. Blakiston's Son & Co. 



r 11 K m a i- 1. E I- k 1 C S S YORK PA 

FEB -A 1921 ©CU608228 
/ 



PREFACE 

Before the foundation of a science is definitely laid, many facts 
must be established, analyzed and correlated. In obtaining 
these facts many methods may be used and many fields studied. 
This is especially true of the science of pharmacology, the founda- 
tion of which rests on anatomy, physiology, chemistry and 
physics. It is natural therefore, in the development of pharma- 
cology, that research should have proceeded in waves, during 
which anatomy, physiology, physics or chemistry, played the 
predominant role. The sequence of such waves may be due to 
the investigator following the line of least resistance or to the 
influence of a dominant character in the science. Finally how- 
ever, such waves are spent, and new methods of attack are 
developed, often in a new field. 

The period of pure physiological methods in which changes in 
blood pressure, respiration or heart rate have been recorded, for 
the present seems spent, and many are convinced that chemistry 
now offers the most hopeful method for the solution of many 
problems of pharmacology. 

The changes in blood pressure, respiration, secretion or meta- 
bolism, after the administration of drugs are fundamentally due 
to a chemical reaction between the drug and the tissue. Physi- 
cal changes also result, and it is often difficult to separate the 
purely physical from the purely chemical. The fact that we 
know little of the chemistry involved in many cases where the 
dynamic reaction is most pronounced cannot be used as an argu- 
ment against the importance of a study of the Chemical Pharma- 
cology. Rather our ignorance of such a reaction should stimulate 
chemical investigation concerning many life processes. The 
dictum of the great physiologist who said " Ignoramus, Ignora- 
bimus," must apparently remain true, until chemical investiga- 
tion gives the explanation. 

The field of Chemical Pharmacology is so immense that it is 
possible to present only a small part of it within acceptable 



VI PREFACE 

limits. However, much of it is co-extensive with Biological 
Chemistry and the aim of this work is to select for emphasis 
those chemical reactions, which, in the various branches, have 
an especial relation to pharmacology. 

The following facts, therefore, have been collected and are 
presented from the point of view of pharmacology, in the belief 
that students of chemistry, pharmacy, biology, and medicine 
should become more familiar with this branch of the subject. 
The writer is also of the opinion that in the teaching of pharma- 
cology, the chemical side should receive much more attention 
than it does at present. In this way the student will have an 
opportunity to review and add to his previous work in chemistry, 
and enter the clinical years better equipped and with a fuller 
appreciation of the most promising avenue of advance. 

In the preparation of this work many sources of information 
have been used. Original papers are not quoted because in an 
elementary work the student wishes a general survey of the field 
and when he attains the stage in which he is able to digest litera- 
ture the sources are readily found. The following works among 
others have been freely used and contain the original references : 
Frankel's Arzneimittel Synthese; The Chemical Basis of Pharma- 
cology — Francis and Fortescue — Brickdale; Cushny, Text-book 
of Pharmacology; Sollmann, Manual of Pharmacology; Richter's 
Organic Chemistry; Mathews, Physiological Chemistry; Henry's 
Plant Alkaloids; Barger, Simpler Natural Bases; Robert's 
Lehrbuch der Intoxikationen ; Armstrong, Carbohydrates and 
Glucosides; Haas and Hill, Chemistry of Plant Products. I 
am especially indebted to my colleague in the department, 
Harry Victor Atkinson, for help in proof reading and for many 
suggestions. 



TABLE OF CONTENTS 

Page 

I. Introduction 1 

Definitions, 1— Classifications, 1 — Organic drugs, 3 — Composi- 
tion of drugs, 4 — Carbon, 4 — Test for hydrogen, 7 — Nitrogen, 7 — 
Test for nitrogen, 8 — Nessler's test, 8 — Kjeldahl's test for nitro- 
gen, 9 — Oxygen, 10 — Ash, 10. 

II. Paraffins . 12 

Properties of the hydrocarbons of the paraffin series, 12 — Crude 
petroleum, 13 — Liquid petrolatum, 14 — Occurrence in nature, 15 
— Synthesis of methane, 16 — Ethane, 16. 

III. Important Drugs of the Methane Series . 17 

Tests for methyl alcohol, 18 — Ethyl alcohol, 19 — Alcohol impor- 
tance of, 20 — The destructive action on the tissues, 21 — Alcohol 

as a food, 21 — The fate of alcohol in the body, 22 — Chemical tests 
for ethyl alcohol, 23 — Lieben's iodoform test, 23 — Ethyl acetate 
test, 23 — -To determine the amount of ethyl alcohol in liquors, 24 — 
Propyl and butyl alcohols, 24 — Amyl alcohol or pentyl alcohol, 
26— Dihydric alcohols, 28— Glycol, 29— Trihydric alcohols, 29— 
Chemical test, 29 — Higher alcohols, 30 — Sulphur alcohols or mer- 
captans, 30 — Pharmacology of the alcohols in relation to their 
chemistry, 31. 

IV. Anesthetics, Narcotics, Soporifics, Hypnotics 32 

Anesthesia, 33 — Anesthetics, 35 — Theories regarding the causa- 
tion of anesthesia, 36 — The Meyer-Overton theory, 36 — The 
theory of Moore and Roaf, 37 — Verworn's theory, 37 — The Hy- 
derabad Commission — 1889 and 1890, 37 — Ether anesthesia, 39 — 
Ether or ethyl oxide, 39 — Chemical tests, 39 — Ethyl chloride, 41 — 
Hypnotics and analgesics of the methane series, 41 — The chloro- 
form group, 41 — Chemical tests, 42 — Phenyl isocyanide test, 43 — 
The urethane group of hypnotics, 43 — Veronal, 44 — Chemical 
tests, 45 — The sulphone group of hypnotics, 45 — Sulphonal, 46 — 
Trional, 46 — Tetranol, 47— Chemical tests, 47. 

V. Aldehydes; 48 

General properties of aldehydes. Reactions, 48 — Tests for for- 
maldehyde, 52 — Liebermah's test, 52 — Rimini's method, 52 — 
Phloroglucinol test (Jorissen), 53 — Phenylhydrazin — HC1 method, 
53 — Phenylhydrazine hydrochloride and ferrocyanic method, 53 — 
Hexamethylenamine, 54 — Acetaldehyde, aldehyde or ethanal, 55 — 



Vlll CONTENTS 

Page 
Paraldehyde, 57 — Chloral and chloraldehyde, 57 — Chloral and 
chloral hydrate, 58 — The fate of chloral in the body, 59 — To test 
urine directly for chloral, 61 — Nessler's solution test, 61 — Chlora- 
lose, 61 — Chemical tests, 61. 

VI. Ketones 62 

Acetone, 62 — Chemical tests, 63 — Legal 's test, 63 — Penzoldt's test, 
63— Reynold's test, 63— Chloretone, 63. 

VII. Organic Acids 64 

Organic acids of methane series, 65 — Acetic acid, 66 — Carbonic 
acids, 67 — Urea, 68 — Oxalic acid, 69 — Malonic acid, 70 — Succinic 
acid, 71 — Tartaric acid, 71 — Citric acid, 73 — Lactic acid, 74 — 
Hydrocyanic acid, 75 — Prussian blue test, 77 — Vortmann's nitro- 
prusside test, 77 — Picric acid test, 77 — General pharmacology of 
the acids, 78. 

VIII. Iodoform and Physiological Substitutes 79 

Lustgarten's test, 80 — Phenylisocyanide test, 80 — Iodoform sub- 
stitutes, 81 — The fate of iodoform in the body, 84 — Bromine com- 
pounds, 85. 

IX. Benzene or Benzol 86 

X. Phenols 89 

Properties of phenols, 90 — Quinol or hydroquinone or para dihy- 
droxy benzene, 92 — Dihydroxy phenols or dihydroxy benzenes, 92 
— Pyrocatechol, 93— Trihydroxy benzenes or trihydric phenols, 
94 — Phloroglucinol, 94 — Pyrogallol or pyrogallic acid, 94 — Cresols, 
95 — Creosote, 97 — Picric acid, 97 — Tests for picric acid, 97 — Re- 
actions of the phenols, 98 — The salol principle, 100 — Friedel and 
Craft's Reaction for Toluene Synthesis, 101. 

XI. Aromatic Alcohols, and Phenol Alcohols 101 

Saligenin, 102 — Aldehydes of the aromatic series, 103 — Benzalde- 
hyde, 103 — Ketones of the aromatic series, 104. 

XII. Acids and Related Compounds 104 

Benzoic acid, 104 — Mesotan, 107. 

XIII. Aniline and Toluene Derivatives 109 

Tests for aniline, 112 — Acetanilide, 112 — Antipyrine or phenyl 
dimethylpyrazolon, 113 — Pyrazolon, 114 — Antipyrine, 116 — 
Pyramidon, 117 — Acetanilide tests, 119 — Tests for antipyrine, 

119 — Salicylic acid tests, 120 — Phenacetin, Acetphenetidine, 120 — 
Saccharin, 121— Thymol iodide, 122— Phenolphthalein, 123— De- 
termination of kidney function, 126. 

XIV. Naphthalenes (tar camphor) 127 

Anthracenes, 128 — Quinones, 130. 



CONTENTS IX 

Page 

XV. Hetero Cyclic Compounds 133 

XVI. Carbohydrates 134 

Monosaccharides, 134 — Disaccharides, 134 — Polysaccharides, 134 

— Difference between starches, gums, celluloses and sugars, 135 — - 
General tests, 135 — Molisch's reaction, 136 — Starches, 137 — 
Tests for starch, 137 — Sugars, 138 — Fermentation, 138 — The uses 
of sugars, 138 — Cellulose, 139 — Tests for cellulose, 140 — Crude 
fiber, 139— Hemicellulose, 140— Agar, 140— Gums, 141— Tests 
for gums, 141 — Pectins, 142 — Method of preparing pectin, 143. 

XVII. Fats and Fixed Oils 144 

Classification of oils, 144 — General properties of fats, 148 — Ex- 
planation of the cleansing action of soap, 149 — The characteriza- 
tion of fats, 151 — Fat constants, 152 — The hydrogen number and 
hydrogenated fats, 154 — The Reichert Meissel numbers, 155 — 
The acetyl number, 155 — The Elai'din test for fats, 156 — The bro- 
mine test, 157 — Maumene or sulphuric acid test, 157 — Rancidity of 
fats, 158 — The significance, uses and fate of fats, 158 — Origin of 

fat in the animal, 160 — Fats from proteins, 162 — The need of 
fats in growth, 163 — The fate of fats in the body, 163. 

XVIII. Waxes 164 

Sterols, 165— Cholesterol, 165— Tests for Cholesterol, 167— Schiff 's 
reaction, 168. 

XIX. Volatile, Ethereal or Essential Oils 168 

Chemical classification, 169 — Aliphatic hydrocarbons in volatile 
oils, 169 — Terpenes, 169 — Aromatic terpenes, 171 — Aliphatic 
alcohols in volatile oils, 173 — Aromatic alcohols in volatile oils, 
173 — Differences between fixed and volatile oils, 173 — The general 
action of the volatile oils, 174 — Action on the alimentary tract, 
174 — Substances excreted combined with glycuronic acid, 175 — 
The significance of glycuronic acid in the urine, 175 — Saponifica- 
tion, 176 — Stearoptenes, 177 — Thymolis iodidum, 179. 

XX. Resins, Ole'oresins, Gum Resins, and Balsams 180 

Oleoresins, 181 — Gum resins, 182 — Balsams, 182. 

XXI. Glucosides or Compound Sugars 183 

Pentosides, Galactosides, etc., 183 — Constitution of the glucosides, 
183 — Glucosides, 185 — Composition of natural glucosides, 188 — 
Ethylene derivatives, 191 — Benzene derivatives, 192 — Phloridzin, 
193 — Styrolene derivatives, 194 — Anthracene or anthraquinone de- 
rivatives, 195 — Saponin or saponins, 196 — The digitalis glucosides, 
196 — Digitalin, 197 — Digitonin, 197 — Convallamarin, 197 — Digi- 
talein, 197— Glycyrrhizin, 197— Scillin, 197— Helleborin, 197— 
Cyanogenetic glucosides, 198 — Solanin, 198 — Coniferin, 199 — 



X CONTENTS 

Page 
Indican, 199 — Indoxyl, 200 — Animal glucosides, 201 — The func- 
tions, action, and fate of glucosides, 202 — Tests for glucosides, 203. 

XXII. Bitter Principles 204 

Tests to distinguish bitters from other bodies, 204 — Pharmacologic 
classification, 204. 

XXIII. Pharmacology of the Taste and Smell 205 

Chemistry and physics of odors, 207 — Taste, 208 — Glucophore, 
212. 

XXIV. Tannic, Digallic Acid or Gallotanic Acid 214 

Fate in the body, 216 — Determination, 218. 

XXV. Neutral Principles 218 

Santonin, 219— Tests, 220— Picrotoxin, 220— Tests, 220— H. 
Meltzer's test, 220— Langley's test, 221 —Physiologic test, 221— 
Elaterin, 221— Chrysorobin, 221. 

XXVI. Alkaloids 222 

Nitrogen bases; plant bases or alkaloids, 222 — General characteris- 
tics of alkaloids, 224 — Chemistry of alkaloids, 225. 

XXVII. Amines or Substituted Ammonias . . '. 225 

Tests for amines, 226 — Quaternary ammonium bases, 228 — Sources 

of amines, 229 — The physiological action of the amines, 230 — 
Amines with two hydroxyl compounds, 232 — Alkaloids derived 
from aliphatic amines, 234 — Epinephrine test, 237 — Arginine, 238 
— The fate of arginine in the body, 238 — Ptomaines or putrefactive 
alkaloids, 239 — Choline, 242 — Ergot alkaloids, 244 — Ergot amines, 
245 — Pyridine alkaloids, 247 — Natural methylated compounds in 
the body, 249 — The fate of creatine and creatinine in the body, 249 
— Tests, 252 — Nicotinic acid, 255 — Tests for nicotine, 255 — Rous- 
sin's test, 255 — Schindelmeiser's test, 256 — Physiological tests, 
256— Strychnine, 256— The fate of strychnine, 256— Tests for 
strychnine and brucine, 257 — Bichromate test, 257 — Physiologic 
test, 257 — Brucine, 257 — Arecoline, 257 — Quinoline, 258 — Quino- 
line alkaloids, 259 — Action, 259 — The fate of quinine in the body, 
259 — Assay of the alkaloids in cinchona bark, 260 — Tests for 
quinine, 261 — Thalleioquine test, IsoquinoHne alkaloids, 261 — 
Hydrastine and hydrastinine, 262 — Hydrastinine, 263 — Hydras- 
tine tests, 263 — Hydrastinine, 264 — Narcotine, 264 — Tests for 
narcotine, 265 — Action of cocaine, 266 — The fate of cocaine in the 
body, 266 — Artificial cocaines, 267 — Tests for cocaine, 267 — The 
pyrrol or pyrrolidine group of alkaloids, 267 — The fate of atropine 
in the body, 271— Tests for atropine, 272— Vitali's test, 272— 
Scopolamine or Hyoscine, 272 — The glyoxaline group of alkaloids, 
273 — Action of pilocarpine, 274 — Fate in the body, 275 — Tests for 
pilocarpine, 275 — Phcnanthrcne alkaloids, 275 — Phenanthrene 



CONTENTS XI 

Page 
group, 275 — Apomorphine, 279 — Apocodeine, 279 — The fate of 
these alkaloids in the body, 280 — Tests for apomorphine, 280 — 
Tests for codeine, 281 — Tests for morphine, 281 — Tests for the- 
baine, 282— Papaverine, 282— Tests, 283— The caffeine group, 283 
— Guanine, 287 — Adenine, 287 — Murexide test, 288 — Action of 
caffeine compounds, 288 — The diuretic action of caffeine, 289 — 
Fate of caffeine in the body, Economic use of caffeine, 291 — Isola- 
tion of alkaloids, 292 — Power and Chestnut's method of assaying 
caffeine in vegetable material, 292 — Isolation of caffeine, 293 — 
Keller's method, 293 — Unclassified alkaloids, 294 — Veratrine, 294 
— Physostigmine or eserine, 294 — Tests, 295 — Colchicine, 295— 
Tests, 295 — Unclassified or alkaloids of unknown composition, 
296 — The physiological significance of nitrogen bases, 297. 

XXVII. Proteins 298 

Classification of proteins, 299 — The simple proteins, 299 — Conju- 
gated proteins, 300 — Derived proteins, 301 — A. Primary products, 
301 — B. Secondary or intermediate protein derivatives, 301 — 
Comparison of animal and vegetable proteins, 302 — Amino acids 
found in plants, 302 — General properties of proteins, 303 — Color 
reactions, 303 — Precipitation reactions, 304 — Hydrolytic products, 
304 — General characters of amino acids, 308— Condensation prod- 
ucts, 309 — Condensation with formaldehyde, 311 — The deamini- 
zation of amino acids, 312 — Urethane formation or the carbo-amino 
reaction of amino acids, 313 — The taste of amino acids, 314 — 
Optical properties of amino acids, 314 — The action of amino acids 
in the body, 315 — The fate of amino acids in the body, 316 — The 
fate of alpha amino acids in abnormal conditions, 319 — Trypto- 
phane, 321 — Poisonous proteins, 322. 

XXVIII. Enzymes or Organic Ferments . 323 

Enzymes used as medicines, 324 — Pancreatic ferments, 324 — The 
fate of enzymes in the body, 325. 

XXIX. Chlorophyll 328 

Relationship of chlorophylls and hemoglobins, 329 — The fate of 
chlorophyll in the body, 333 — Other plant colors, 333. 

XXX. Colloids 335 

Character, or nature, of colloids, 336 — Classification, 338 — Dif- 
ferences between the suspensoid and emulsoid colloids, 338 — Gel 
formation, 339 — Lyotrope series, 340 — Electric conditions of col- 
loids, 341 — Protective power of colloids, 342 — Change in colloids 
in gel formation and precipitation, 342 — Surface tension, 343 — 
Viscosity and surface tension, 345 — Superficial viscosity, 347 — 
Relation of composition to surface tension, 347 — Relation of com- 
position to viscosity, 348 — Adsorption, 349 — Selective adsorption, 
349 — Influence of salts on absorption, 349. 



Xll CONTENTS 

Page 

XXXI. The Reaction of Living Matter 350 

The colorimetric method, 351 — Electro potential method or gas 
chain method, 351 — Method of expressing hydrogen ion concentra- 
tion, 352 — Regulating mechanism, 354 — Actual and potential al- 
kalinity and buffer value, 355 — Potential alkalinity of blood, 356 

— Acidosis, 357 — The determination of the existence of acidosis, 
359 — Tolerance to carbonate, 359 — Urinary changes, 360 — 
Lowered tension of carbon dioxide in the respired air, 360. 

XXXII. Phosphorus 361 

The fate of phosphorus in the body, 364 — Arsenic compounds, 
364 — Fate of arsenic in the body, 367. 

XXXIII. Heavy Metals 368 

Explanation of precipitation, 369 — Colloidal metals, 372. 

XXXIV. Inorganic Acids 373 

XXXV. Salt Action 374 

Diffusion, 375 — Osmosis, 375 — Gas pressure in relation to osmotic 
pressure, 375 — Difficulties in determining osmotic pressure, 376" — 
Relation of osmotic pressure to the boiling point and freezing point 

of solutions, 377 — Freezing point method, 377— To calculate the 
osmotic pressure from the freezing point, 377— Salts in the body, 
378 — Salt action in pharmacology, 379. 

XXXVI. Toxicology 379 

The isolation of poisons, 379 — Apomorphine, 381 — Methods of 
isolating poisons, 382 — The isolation of volatile poisons, 382 — 
Preliminary test for phosphorus, 382 — Discussion of results, 382 — 
Mitscherlich's test, 383 — Ammonium-molybdate test, 385 — 
Ammonium magnesium phosphate test, 385 — The Mitscherlich- 
Scherer method for the qualitative and quantitative estimation of 
phosphorus, 386 — Tests for detection of phosphorus in oils, 387 — 
Acetone, 387 — Aniline, 387 — Oil of bitter almonds or benzalde- 
hyde, 387— Test for KCN, 387— Carbon bisulphide, 388— Chloral 
hydrate, 389— Ethyl alcohol, 389— Methyl alcohol, 390— Iodo- 
form, 390 — Nitrobenzene, 390 — Phenol, 390 — Quantitative esti- 
mation of phenol, 390 — Creosote (Creosols), 390 — Non-volatile 
organic poisons, 391 — Acid extraction Stas-Otto method, 392 — 
Metallic poisons, 394 — Arsenic test, 396 — Detection of antimony, 
397 — Differences between arsenic and antimony, 398 — Test for 
mercury, 398 — Examination of the nitric acid solution, 399 — 
• Copper and bismuth tests, 399 — Chromium and zinc, 399 — Synop- 
sis of metallic poisons, 400 — Sulphuric acid, 401 — Nitric acid 
tests, 401 — Oxalates and oxalic acid, 402 — Alkalies, 403 — Fixed al- 
kalies, 403 — Potassium chlorate, 403 — Active substances which find 
no place in the Stas-Otto method, 403 — Santonin, sulphonal; trional, 
404 — Digitalis, 405 — Ergot, 405 — Reagents and solutions, 406. 



CHEMICAL PHARMACOLOGY 

I. INTRODUCTION 

Pharmacology is the science which deals with drugs and the 
reactions of living matter brought about by drugs. The term, 
"drug" is derived from the Dutch or Anglo-Saxon word, "drugan," 
meaning to dry, and was formerly applied to dried medicinal 
plants. At that time materia medica was entirely of plant origin, 
at present the term includes all substances used as remedial 
agents. 

It is often desirable to define foods, drugs, and poisons; but 
the distinctions at best are unsatisfactory and arbitrary. Foods 
are substances, which, when taken into the alimentary tract are 
digested, build up tissue, supply energy, repair waste, and do not 
injure health. A poison is anything that, in amounts of fifty ^7 
grams or less, injures or destroys life, when taken by mouth. V 
There is, however, no satisfactory definition of a poison, and 
fifty grams is an arbitrary amount; some set the limit at one 
gram. Drugs and poisons are relatively little acted on by the 
body, are but little digested or hydrolyzed, and as a rule do not 
supply energy, and do not repair waste. Some substances, may 
be remedies, foods, or poisons, according to the method of adminis- 
tration; e.g. egg albumen and peptone, are foods when taken 
by mouth, but they are violent poisons if given intravenously. 
Iron salts too, when taken by mouth are valuable remedies in 
some cases of chlorosis, but they also may exert a toxic action if 
given by vein. Some foods such as milk, fish and strawberries 
produce most violent toxic symptoms, when taken even in 
small amounts, in some persons who are said to have an idiosyn- 
crasy for those particular substances. 

Classifications. — Drugs may be classified as: 

1. Inorganic or mineral 

~ . [Animal 

2. Organic 



Vegetable 

or as was done by chemists about the middle of the 17th Century, 
as animal, vegetable, and mineral. 

1 



I CHEMICAL PHARMACOLOGY 

When it was discovered that certain compounds are found in 
both animals and plants, the distinction between animal and 
vegetable chemistry disappeared and to include both the broader 
term " organic " was substituted. It was believed then that 
" vital force" was necessary for the formation of organic com- 
pounds, and that these could not be produced by the chemist. 
In 1828, however, Wohler prepared the organic substance, 
"urea" from the so-called inorganic compound, ammonium 
isocyanate : 

. /NH 2 
NH 4 CNO = CCxf 

X NH 2 
Ammonium isocyanate urea 

Since this discovery a sharp distinction between organic and 
inorganic compounds cannot be made. Yet, the term "organic" 
has survived, and includes not only those substances formed in 
plants and animals, but also most carbon compounds. Many 
synthetic drugs which contain carbon, are in reality no more 
organic than calcium carbonate, but are included in organic 
chemistry because of relationship, or of historical interest. 

The term vital force or vital activity is still used by physiolo- 
gists and pharmacologists especially in discussing absorption and 
secretion. It means simply that the known physics and chemis- 
try is inadequate to explain all the phenomena, and that the 
explanation of some life processes is still unknown. 

In addition to carbon, the chemistry of drugs includes other 
important elements. Twelve elements are necessary for life 
and are consequently found in varying amounts in all organic 
matter. These elements are: C, H, N, O, S, P, Na, Mg, Ca, Fe, 
CI, and K. If any of these elements be extracted from living 
matter, death results. 

If the amount of each element in a substance is determined, 
we say that the analysis is ultimate. The elements however do 
not exist in a free state in plants or animals, but are combined to 
form fats, proteins, carbohydrates, volatile oils, gums, gum resins, 
alkaloids, glucosides, salts, etc. These, when they are definite 
chemical compounds, are called proximate principles, and the 
determination of the amount of these substances is proximate 
analysis. 



PKOXIMATE PRINCIPLES 



Proximate principles because of their reaction are divided into 
acid, neutral, and basic principles. The following scheme is 
illustrative : 

Organic Drugs 
Animal Vegetable 

\ m / 

Proximate Principles 

i 

1. Proteins 

' Fats 

2. Lipoids or ether extracts \ , , , . 

cholestennes 

waxes 

Celluloses 

dextrin 

gums 

3. Carbohydrates j sugars 

pectins 

starches 

glycogen 

4. Alkaloids 

5. Glucosides — which include saponins and sapotoxins. 

6. Volatile, ethereal, or essential oils. 



7. Stearoptenes . 



Camphor 

menthol 

thymol 



8. Resins 



oleoresins 



gum resins 
balsams 
9. Organic acids. 

10. Coloring matter or pigments. 



Chlorophyll 

carotin 

xanthophyll 



11. Ash or inorganic residue which remains when drugs or 
plants are ignited to constant weight at red heat. 

While according to their reaction these bodies are acid, basic, 
or neutral; the term "neutral principle" is often used in a different 



4 CHEMICAL PHARMACOLOGY 

sense. It is applied especially to those neutral physiologically 
active bodies that do not belong to a more definite chemical 
class; e.g. picrotoxin is a neutral principle and is known only by 
that term. Glucosides are also neutral, but are rarely referred 
to as such, because the term, "glucoside" is more specific than 
"neutral principle." An alkaloidal salt may be neutral in reac- 
tion but is never referred to as a neutral principle, but is always 
classified with alkaloids. 

Proximate principles, when acted upon by bacteria, yeasts, 
enzymes, heat or chemical agents, give rise to pure chemicals of 
simpler composition such as paraffins, alcohols, ethers, acids, 
etc., and these form the basis of organic chemistry. Many of 
these chemicals are used in medicine, and a knowledge of the 
structure of the simple organic bodies is essential for a study of 
the more complicated proximate principles, and for the study 
of pharmacology. Pharmacology in the last analysis is ap- 
plied organic chemistry, or the chemistry and reactions of living- 
matter, as modified by changes in environment. The cause of 
these changes whether due to noxious gases, decomposition 
products of foods, impurities in water, bacterial toxins or 
other injurious or modifying agent in the widest sense comes 
under the term "drug." However, the study of pharmacology 
is usually limited to those drugs that are used in therapeutics, 
or that are especially valuable in investigative work. 

THE COMPOSITION OF DRUGS 

CARBON 

Carbon in the elemental condition, and in the form of CO, C0 2 
and the carbonates is included in inorganic chemistry. All other 
carbon compounds are, for convenience, classified under organic 
chemistry. 

The word, "carbon" is derived from the Latin, "carbo, " 
meaning coal, and the ordinary test for carbon is the carbonizing 
action or the becoming coal-like on burning. If we partially burn 
a piece of wood, paper, or almost any organic substance it chars. 
There is a similar action, if we add strong sulphuric to it. The 
acid extracts the water part of the molecule leaving carbon 
partially free, or charred. If enough oxygen is present in the 



CARBON O 

molecule, or if burning continues, the carbon is completely oxi- 
dized and disappears as a gas, CO or CO2, but always as CO2 if 
enough oxygen be present. Most carbon compounds when 
taken into the body are oxidized in a similar way, but the oxi- 
dative potential of the body is not sufficiently high to oxidize 
elementary carbon, nor even such compounds as cellulose. 

Not all organic compounds carbonize on heating. If oxalic 
acid, COOH. COOH, be heated, it breaks down into C0 2 , CO and 
H 2 without charring. The reason being that it contains enough 
oxygen in the molecule, to completely oxidize the carbon present. 
The form in which carbon occurs in the molecule is also an im- 
portant factor in determining whether or not it will carbonize on 
heating. When present in the form of carboxyl, as it is in the 
case of oxalic acid, it is already oxidized and in a bound or 

•° 

gaseous form — C<^ so that carbonization is impossible 

X OH 
since it is already past that state. It may break either as 

/> 

H — Q{ — * H 2 + CO in which case, the water is split 

\)H 
directly from the molecule; or in oxalic acid it may break into 
CO2 and H 2 0, the H in the acid being oxidized to water by the 
oxygen of the air; 

COOH 

1 / ~ ■ 

COOH + = 2C0 2 + H 2 

There is a general tendency of organic acids, especially when 
heated under the influence of strong dehydrating agents, to 
break up, giving off C0 2 or CO from the carboxyl group : e.g. 

Formic acid HCOOH + H 2 S0 4 = CO + H 2 

Malonic acid heated to 140° COOH 
yields acetic acid and C0 2 

CH 2 = CH 3 COOH + C0 2 

COOH 



CHEMICAL PHARMACOLOGY 



In case of aliphatic compounds, the tendency to yield C0 2 is 
greater where two carboxyl groups are attached to one carbon 
atom. 



COOH 



OH 



Gallic acid when heated 
yields pyrogallic acid and 
OH carbon dioxide OH 



OH OH 



+ CO 



OH 



For these reasons carbonization is not a general test for organic 
substances. The formation of CO2 is a more definite test. 

The presence of carbon can be shown in those cases that do 
not char, if the gas evolved on heating be collected in NaOH or 
Ca(OH) 2 ; this results in the formation of a carbonate 

2NaOH + C0 2 = Na 2 C0 3 + H 2 
or Ca(OH) 2 + C0 2 = CaC0 3 + H 2 

The presence of C0 2 in the respired air can be shown this way. 
The formation of a carbonate is a general proof of the presence 
of carbon whether or not there be carbonization. 

Carbon, prepared by heating bone — bone charcoal, or wood — 
wood charcoal, in absence of air or oxygen, is used in medicine in 
some cases of stomach disease, and in other cases, as an absorbent 
of gases. It will also absorb toxins as in diphtheria, and has 
been sometimes applied locally for this purpose. It is used in 
chemical analysis as a clarifying agent to absorb colors. When 
carbon is wet its value as an absorbent for gases is greatly les- 
sened, for this reason, its value when given to absorb gases in 
the stomach is questionable. 

Carbon dioxide in the body is the specific stimulus of the respi- 
ratory centre. It is generated by the oxidation of the carbon of 
the food. The fate of carbon and hydrogen is very important 
since in the body the oxidation of the carbon and hydrogen of 
the food is the exclusive source of heat and therefore of body 
temperature. The calorific value of foods in the body is the same 
as they yield in the calorimeter, but in the body oxidation pro- 



HYDKOGEN AND NITROGEN / 

ceeds at about 40°C. while in the calorimeter high temperatures 
are necessary to complete the oxidation. 

Test for Hydrogen 

The presence of carbon and hydrogen together in drugs or 
organic compounds can be shown by heating the dried material 
with desiccated copper oxide in a glass tube. The copper oxide 
is reduced in the presence of organic matter and the free 
oxidizes the C and H to C0 2 and H 2 0. The C0 2 is detected in 
the usual way with lime water. The water formed will condense 
in the cold part of the tube in which the substance is heated. 
The formation of water is proof of the presence of hydrogen. 
If desired, the water so formed may be collected in sulphuric 
acid and weighed as is done in ultimate analysis. Hydrogen in 
the free form is not used in medicine. 



NITROGEN 

Nitrogen as a free gas is characterized by its chemical inertness. 
A burning splinter immersed in a vessel containing nitrogen 
gas is immediately extinguished. Animals and plants die if 
confined in an atmosphere of nitrogen. For this reason, it was 
formerly called Azote (against life) . It is a constant constituent 
of all plants and in combination is an indispensible food. It is 
also essential in the air as a diluent of oxygen, since life in pure 
oxygen is impossible. Because of its inertness, the gas has been 
used in therapeutics, in the pleural cavity, to collapse one lung 
in case of tuberculosis of that organ; the idea being to rest the 
lung by collapse and so permit healing, also by preventing move- 
ment, to lessen the tendency to spread the diseased condition. 
Nitrogen in plants exists mainly in the form of: 

1. Proteins 9. Some glucosides 

2. Amino acids 10. Mixed compounds, etc. 

3. Amines 

4. Alkaloids 

5. Phosphatides 

6. Nitrates 

7. Cyanides 

8. Ammonia 



8 CHEMICAL PHAKMACOLOGY 

To determine whether or not, a drug or any organic matter 
contains nitrogen, the following tests may be used : 

Test for Nitrogen 

1. In many cases, when an organic substance is burned, an 
odor like burnt feathers is given off; this is characteristic of the 
presence of N. 

2. Lassaigne's test: Organic bodies always contain carbon, 
therefore if a small amount of the substance be heated in a dry 
test tube to redness, with Na, or K, and the test tube be im- 
mediately plunged into water in a beaker, the C and N, if present, 
will combine with the Na, or K to form KCN or NaCN, which 
may be detected by treating with a mixture of ferric and ferrous 
salts, Prussian blue being formed. 

Freshly prepared ferrous sulphate with a drop or two of ferric 
chloride added, is a suitable reagent. During the operation some 
ferrous hydrate is converted into ferric hydrate, which when 
acidified with HC1 is converted into ferric chloride. The reac- 
tions may be illustrated as follows : 

1. 2C + 2N + 2K->2KCN 

2. 6KCN + FeS0 4 -> K 4 Fe(C!N) 6 + K 2 S0 4 

3. Fe 2 Cl 6 + FeS0 4 + 8NaOH -> Fe 2 (OH) 6 + Fe(OH) 2 + 

6NaCl + Na 2 S0 4 

4. 2Fe 2 (OH) 6 + 3K 4 Fe(CN) 6 + 12HCl-^Fe 4 {(Fe)(CN) 6 } 3 + 

12KC1 + 12H 2 
Or 

1. FeS0 4 + 2KOH = Fe(OH) 2 + K 2 S0 4 

2. Fe(OH) 2 + 2KCN = Fe(CN) 2 + 2KOH 

3. Fe(CN) 2 + 4KCN = K 4 Fe(CN) 6 

4. 2Fe 2 Cl 6 + 3K 4 (Fe(CN) 6 ) = Fe 4 {Fe (CN)«|, + 12KC1 

If the blue or green color does not quickly develop, a drop of ferric 
chloride should be added. It often happens that not enough 
Prussian blue is formed to give the blue color. The formation 
of a green solution is sufficient proof. 

Nessler's Test. — Nessler's reagent produces a brown precipitate 
of NHg 2 I. H 2 in solutions containing ammonia. If only a trace 
of ammonia be present a yellow or reddish yellow color is pro- 
duced. This reaction is used to determine ammonia in water. 



NITROGEN TESTS 9 

3. Kjeldahl's Test for Nitrogen. — Also the estimation of the 
amount of nitrogen. This test consists essentially in boiling the 
organic substance with strong H 2 S0 4 which destroys the organic 
matter and converts the nitrogen into (NH 4 ) 2 S0 4 ; this is then 
tested for NH 3 which if present, proves the presence of nitrogen. 
The method here described is the most used one for determination 
of the amount of nitrogen, and protein material in drugs, foods, 
and other products. It is carried out as follows: 

Place 1 to 5 grams of the dry material, accurately weighed in 
a Kjeldahl flask of about 500 cc. capacity. Add 30 cc. 
H 2 S0 4 cone, and about 0.5 gram mercuric oxide, or pure mercury. 
The mercury acts as a catalytic agent and hastens oxidation. 
Boil over a free flame until the solution is a pale straw color, white 
or clear water color. Sometimes the substance, on boiling, 
bumps; to prevent this, kaolin, zinc or other finely divided inert 
material is added, which prevents bumping by stirring the mix- 
ture so that the heat is uniformly distributed and no point of the 
glass becomes heated to a much greater extent than the rest. 
Many substances foam so much on heating that paraffin or some 
other substance is added to lesseu this. After the substance 
has boiled until it is milky or water color, the flask is removed 
and about 0.5 gram of KMn0 4 added, to complete the oxidation. 
The nitrogen is now in the form of (NH 4 ) 2 S0 4 , which has been 
proved by isolation and analysis of the crystals. An excess of 
strong NaOH added to this solution liberates NH 3 , which may be 
distilled and caught in a solution of acid of a known strength and 
titrated, e.g., (NH 4 ) 2 S0 4 + 2NaOH = Na 2 S0 4 + 2NH 4 OH. 
If we collect this, say in 50 cc. of N/10 H 2 S0 4 we know how much 
NH 3 is present by titrating the excess of the acid with N/10 
NaOH. 1 cc. of N/10 H 2 S0 4 = .0017 grams NH 3 or .0014 
grams N. For example: one gram of a substance treated as 
above, with H 2 S0 4 was made strongly alkaline and distilled into 
50 cc. N/10 H 2 S0 4 . When this distillate was titrated with N/10 
NaOH it was found that it took 20 cc. NaOH to neutralize. 
Therefore, the nitrogen in one gram of the substance is equiva- 
lent to 50 cc. N/10 - 20 cc. N/10 = 30 cc. N/10 acid. Since 
1 cc. N/10 acid = .0014 grams N, 30 cc. = 0.042 grams N or 
the amount in one gram of the substance and the percentage 
is 100 times 0.042 = 4.2 per cent. 



10 CHEMICAL PHARMACOLOGY 

Since protein contains on the average of 16 per cent. N, it is 
customary to multiply the amount of N by 6.25 to obtain the 
per cent, of protein (6.25 times 16 per cent. = 100 per cent.). 
All protein, however, does not contain exactly 16 per cent, nitro- 
gen, so that in some cases the factor 6.25 is not exact. 

Various non-essential details in the method are used in some 
cases, such as the addition of potassium sulphate to raise the 
boiling point and the addition of other catalytic agents. 

OXYGEN 

Oxygen. — In addition to carbon, hydrogen and nitrogen most 
organic compounds also contain oxygen. Because these elements 
occur so universally in organic matter, they have been called or- 
ganogens. This term has also been used to include the other 
essential ingredients of plants. The well known chemical prop- 
erties of oxygen in the gaseous form cannot be demonstrated in 
organic bodies. There is no simple practical method for its 
direct determination. Its quantity is usually calculated in 
analyses by the difference between 100 per cent, and the sum of the 
percentage of the other elements present, after the other elements 
have been determined. Ever since the importance of oxygen 
became known, attempts have been made to use it in failing respi- 
ration. As a rule, however, it is of little value, because in most 
cases the asphyxiation that suggests its use, is really due to a 
failure of the heart. Again the hemoglobin of the blood, which 
is the oxygen carrier to the tissues, is in most cases saturated, 
so that the administration of pure oxygen can aid but little. In 
cases of severe hemorrhages or of poisoning carbon monoxide, 
nitrites, chlorates, nitrobenzol, etc. which destroy the oxygen 
carrying power of the blood, it has been shown that when pure 
oxygen is administered the oxygen content of the red cells and 
serum is increased somewhat, and this slight increase may be 
very beneficial. If the gas be administered under tension there 
may be sufficient oxygen increase in the blood to cause convul- 
sions in animals. Hilarity and other nervous influences have 
been observed in man. There is some increase in metabolism 
but not sufficient to be of benefit in any given case. 

Ash. — If an organic substance contains C, H, N, and O only, 
it will leave no residue or ash on burning. Plant drugs leave 



ASH 11 

an ash which contains varying amounts of Na, K, Mg, Ca, CI, P, 
S, Si and Fe, as necessary ingredients. Depending on the soil 
on which they were grown, plants may also contain As, Ba, Mn, 
Ij Zn or any other element, not as essential, but as accidental 
elements. 

Before testing for these elements, it is necessary to reduce the 
plant or drug to an ash. The organic matter must be completely 
destroyed because the inorganic elements react only as ions and 
ionization is prevented and masked by organic matter. 

To aid in the "ashing" some oxidizing agent which can be 
driven off by heat may be used, e.g., H2O2 — HNO3, etc. or, in 
case we do not wish to test for K, or CI, KCIO3 may be used. A 
small amount of any of these agents aids oxidation and the reduc- 
tion of the substance to a white or grey white ash. The ash of 
plants is rarely pure white because of the presence of iron, and 
other elements. After the ash has been prepared, it is dissolved 
usually in dilute HC1 and tests for the elements made with the 
solution. The following scheme will show how to prepare the 
ash of plants for analysis. 

Weigh out 5 grams of the root, leaves, or whatever is to be 
determined, and place in a platinum or porcelain crucible or 
dish. Heat it gradually on a thin sheet of asbestos over a Bun- 
sen burner. In order to avoid loss by volatilization, tilt the 
dish or crucible, and at the beginning keep it covered. The 
material first chars, then glows beginning at the top and gradu- 
ally extending to the bottom. Carefully regulate the heat to a 
dull redness (about 700°C). If heated higher than this, there 
is a loss of alkali chlorides by volatilization and the phosphates 
fuse about the particles of carbon, so that this cannot be oxidized 
completely. A muffle furnace may be used to complete the oxida>- 
tion. Finally, when the ashing is complete, weigh and calculate 
the amount. 

In an actual determination, several weighings are made, and 
the substances heated between these weighings, until the weight 
keeps constant. We know then that oxidation is complete. 

The ash of plants contains considerable carbon dioxide, which 
may be found with sodium, potash, or any of the other elements, 
in the form of a carbonate and imparts to the ash an alkaline 
reaction. The use of plant ash in earlier times for the formation 



12 CHEMICAL PHARMACOLOGY 

of soap, is due to this fact. In the analysis of an ash, therefore, 
we determine the amount of CO2, sand, silica, Fe, Al, Ca, Mg, 
and acid radicals, SO3, P2O5, etc. These are in very small 
amounts and while absolutely essential to the life of the plant, 
and in the main, essential ingredients of foods, they are not 
present in sufficient amount to be important as drugs. 



II. PARAFFINS 

The paraffins are prepared from crude petroleum or rock oil 
(petros-rock) which in turn is the result of the decomposition of 
organic matter. Because of their inertness the name paraffin has 
been applied (parurn-small, affinis-affinity) . The series is known 
by a number of names: 

1. Fatty or aliphatic because the best known fats belong 
chemically to it (aliphos, fat). 

2. The limit series because the valences of the carbon atoms are 
saturated to the limit. 

3. It is called the chain series or acyclic because the carbon 
atoms are supposed to be arranged in the form of a chain 



in contra-distinction to the ring, or benzene series. 

4. Since methane, CH 4 , is the first member, it is also known 
as the methane series. Because methane is found in nature in 
marshes, the term marsh gas series is also used. Members of 
from 1 to 60 carbon atoms are known. 

All hydrocarbon compounds are grouped under three heads, 
namely : 

1. Fatty or acyclic, or chain-like carbon derivatives. 

2. Carbocyclic, or aromatic compounds. 

3. Heterocyclic compounds. 

Properties of the Hydrocarbons of the Paraffin Series. 
Those containing from 1 to 4 carbon atoms are gases; from 5 to 16 
Liquids; and those containing more than 16 carbon atoms are 
solids. This statement refers to ordinary temperatures and 



PARAFFINS 13 

pressures. All of them may be converted into gas, or all into 
solids, if the temperatures and pressure conditions are controlled. 

The paraffins are saturated, therefore, they do not absorb 
bromine or hydrogen and are not absorbed by sulphuric acid. 
They are insoluble in water; the lower and intermediate members 
are readily soluble in alcohol and ether. They are noted for 
their chemical and pharmacologic inertness. Their action 
in the body is mainly physical. However, such light distillates 
as naphtha and benzine, are excellent solvents for fats, oils, 
lipoids, resins, and their volatility aids absorption. These light 
distillates often produce toxic effects that can be ascribed to 
their action on the nervous system, probably due to a solvent 
action on lipoids. Following their administration, headache, 
nausea, giddiness, unconsciousness, muscular tremors, convulsions, 
cyanosis and death, have been observed. 

The irritant effect of the lighter members may also produce 
gastritis and gastro-enteritis. When the boiling point reaches 
that of kerosene, the toxicity is greatly diminished. Gastro- 
enteritis and narcotic effects similar to alcohol have been ob- 
served after kerosene, but no deaths have been reported, although 
cases are reported where as much as a liter was swallowed. Liquid 
petrolatum has an emollient effect. The solids are inert. 

A few hydrocarbons, benzine, gasoline, kerosene, vaseline, 
liquid petrolatum, and solid paraffin are used in medicine. 
One should carefully distinguish between benzine, and benzene. 
Benzine is a light paraffin, a mixture of CeHu and C7 His, while 
benzene or benzol, C 6 H 6 , is an aromatic compound, It (benzol) 
has recently had considerable vogue in the treatment of leukae- 
mia. Small amounts of it (1 cc. dose) reduce the number of 
white cells in the blood, but its continued use is fatal. Kerosene 
is used especially in dispensary practice to rid the hair of nits 
and lice. 

The hydrocarbons above mentioned differ mainly in their 
physical properties, but there is some chemical basis for this dif- 
ference. The source of all these is crude petroleum. 

CRUDE PETROLEUM 

This is a most important source of the paraffin hydrocarbons. 
When distilled at varying temperatures, the different fractions 



14 CHEMICAL PHARMACOLOGY 

have a varying and mixed composition, but are approximately as 
follows : 

Distillation at temperature of: Gives as a resulting substance: 



0° 




Gases, which may be liquified 
under pressure, CH 4 to C 4 H* 


18° 




Rhigolene, C 5 Hi 2 — C 6 Hi 4 


50° 


and 60° 


Petroleum ether, or naphtha, 
CeH 14 — C7H16 


70° 


and 90° 


Benzine, a mixture of C 6 Hi 4 
and C7H16 


90° 


and 120° 


Ligroin, C 7 Hi 6 and C 8 Hi 8 


120° 


and 150° 


Petroleum benzine, C 8 Hi 8 — 
C10H20 


150° 


and 300° 


Burning oil distillate kerosene 



From the residue left after distillation at 300°, liquid paraffin, 
vaseline, and solid paraffin are prepared. These are essentially, 
paraffins that distil between 300° and 390°C. 

LIQUID PETROLATUM 

Liquid petrolatum may be obtained from petrolatum after 
the fractions distilling under 330° have been removed. The re- 
maining liquid, when distilled between 330° to 390°, gives liquid 
petrolatum which is purified by treating with sulphuric acid, and 
then by caustic soda, and by filtering while hot through some 
decolorizing agent, like animal charcoal or Fuller's earth. It 
is used in medicine as a cathartic and as a vehicle for other drugs. 

Petrolatum, U. S. P. or petroleum jelly, is a soft paraffin or 
vaseline obtained from the liquid paraffin distillate. The part 
solidifying at 38°-54° is called petrolatum or vaseline. 

Paraffin durum, or hard paraffin, is chemically similar to vase- 
line, but has a higher melting point, 50°-57°, hence it will cry- 
stallize out of the distillate before vaseline. It is prepared in the 
cakes of commerce by pressure, and on account of its inertness is 
used in the laboratory around the stoppers of acid and alkali 
bottles. It has been used by " beauty specialists " to remedy 
minor deformities by injecting under the skin, a procedure which 
is not recommended. 

tight liquid petrolatum (petrolatum leyjs) is used as a vehicle 



PETROLEUM 15 

especially for nasal and throat sprays. It is itself an emollient 
and as such serves to soothe, and to protect inflamed mucous 
membranes, and at the same time mild antiseptics like menthol 
or eucalyptol are incorporated with it. A popular nasal spray 
or nebula consists of one per cent, each of menthol and eucalyptol 
in light liquid petrolatum. 

Liquid petrolatum (heavy-Petrolatum ponderosum or gravis) 
is used as a cathartic and is very servicable where a .cathartic 
has to be given continuously as in chronic constipation and 
certain diseases of the intestine. It acts mechanically. Any 
non-absorbable fluid may act in the same way. It is valuable in 
these cases, because it does not cause griping, and does not be- 
come inert through continual use. The physical difference be- 
tween light and heavy petrolatums is mainly a difference of 
viscosity. 

The following tables show how the boiling point changes as the 
molecular weight increases. 

Substance 

Methane 

Ethane 

Propane 

Butane 

Pentane 

Hexane 

Eicosane 

Penta tria contane 

Dimyricyl 

OCCURRENCE IN NATURE 

Methane, or marsh gas, CH 4 , the first of the series, is found 
in marshes and coal mines in varying amounts, and wherever 
decomposition of vegetable matter in lack of oxygen occurs. 
Mixed with air, methane is known as the fire damp of mines. It 
is one of the gases of the intestine, and in smaller amounts may 
be found in respired air. It may be prepared synthetically in a 
number of ways. These methods have little direct interest in 
pharmacology, but since they are fundamental and illustrate how 



VEolecular 


Boiling 


formula 


point 


CH 4 


-164° 


C2H6 


- 84° 


C3H8 


- 45° 


C4H10 ",j 


1° 


C5H12 


36° 


CeHi4 


70° 


C20H42 


330° 


C35H72 


331° 


C60H122 





16 CHEMICAL PHAKMACOLOGY 

paraffins may be formed from the elements they are briefly 
indicated : 

SYNTHESIS OF METHANE 

I. Hydrogen sulphide and carbon bisulphide passed through 
a red hot tube containing copper, yield CH 4 . 

2H 2 S + CS 2 + 4Cu = 4CuS + CH 4 

II. By passing carbon monoxide and hydrogen over reduced 
nickel at 200°C. 

CO + 3H 2 = CH 4 + H 2 

III. At 250°C, C0 2 is also reduced in the presence of finely 
divided nickel. 

C0 2 + 4H 2 = CH 4 + 2H 2 

IV. Methyl alcohol or wood spirit can be converted into 
methane by changing to methyl iodide and then (a) the iodide 
nascent hydrogen: 

CH3OH + I 2 + 2H = CH3I + H 2 + HI or (b) 
CH3I + 2H = 2CH 4 + HI 
These and many other methods are used for preparing methane. 
Methane itself has no uses in medicine. The most important 
derivatives of methane from a pharmacological point of view, are 
methyl alcohol because of its toxicity and as a source of form- 
aldehyde. The latter is used because of its antiseptic action. 

ETHANE 

This is the second member of the paraffin or methane series. 
It occurs in small quantities in natural gas and crude petroleum. 
Its derivatives only are important. It may be prepared synthe- 
tically in a number of ways, which show that it is made up of two 
methyl (CH 3 ) groups, as the following reaction shows: 
2CH 3 I + 2Na = CH3.CH3 + 2NaI 
Ethane is also formed when ethylene is treated with nascent 
hydrogen : 

C 2 H 4 -\- 2H = C 2 He 
or when ethyl iodide is treated with hydrogen 
C 2 H 6 I + 2H = C 2 H 6 + HI 
while ethane is not used in medicine its derivatives are exceedingly 
important. 






METHANE SERIES 



17 



IMPORTANT DRUGS OF THE METHANE SERIES 
III. ALCOHOLS 

The drugs of the methane series includes alcohols, ethers, 
ketones, and many derivatives which are used as narcotics or 
hypnotics. 

Alcohols are hydroxyl derivatives of the marsh gas series (cf. 
phenols) . According to the number of hydroxyls in the molecule 
they are classified as: 

1. Monatomic or monhydric 

2. Diatomic or dihydric, etc. 

No gaseous alcohols are known. Up to C12H25OH with few 
exceptions they are neutral, colorless liquids with a pleasant odor 
and burning taste. The more important members of the mon- 
hydric alcohols with their boiling point and specific gravity are 
as follows: 



Substance 



Chemical 
formula 



B. P. 



Spec. 
Grav. 



Relative 

toxicity 

(Baer) 



Methyl alcohol 
Ethyl alcohol. . 
Propyl alcohol. 
Butyl alcohol. . 
Amyl alcohol. . 



CH 3 OH 
C 2 H 5 OH 
C 3 H 7 OH 
C 4 H 9 OH 
C 5 H n OH 



66° 

78° 

97° 

117° 

131° 



0.812 
0.806 
0.817 
0.823 
0.825 



0.8 (?) 

1. 

2. 

3. 

4. 



Ethyl alcohol is the only one that is used in medicine to any 
degree. Methyl and amyl alcohols are of importance because of 
their toxicity. The relative toxicity given by Baer does not 
hold good for all forms of life. It is only approximate at best. 
For man, it is incorrect, methyl being more toxic than ethyl. 
As we ascend in the alcoholic series, the members soon become 
more solid, and much less soluble, hence less toxic. A drug that 
is insoluble in the tissues or fluids of the body is inert. However, 
many substances that are insoluble in water dissolve readily in 
the body fluids. Next to water, alcohol is the solvent that will 
dissolve the greatest number of substances. 

Methyl alcohol, or wood spirit, is prepared on a large scale by 

the dry distillation of wood. It is important in medicine chiefly 

because many cases of poisoning have arisen from its use. Its 
2 



18 CHEMICAL PHARMACOLOGY 

actions in general are the same as ethyl alcohol, and are exerted 
mainly on the central nervous system. It seems to have a 
selective action on the optic nerve, and blindness often follows 
its use; even one dose of about 60 Cc. has caused permanent 
blindness. Many such cases have been reported recently. 
In repeated doses it is much more toxic than ethyl alcohol. It 
has been used in patent medicines because it is cheaper than 
ordinary alcohol. Its use, however, should be condemned 
unhesitatingly. 

The main differences in the intoxication of methyl and ethyl 
alcohols are: The coma produced by methyl alcohol may last 
for several days, as compared with a few hours in case of ethyl 
alcohol. Methyl alcohol readily attacks the optic nerve and may 
cause the blindness, which is absent in the action of ethyl alcohol. 
The oxidation products of methyl alcohol, formaldehyde and 
formic acid, are prone to irritate the kidneys and bladder, con- 
sequently nephritis and cystitis are frequent after wood alcohol 
poisoning. 

Tests for Methyl Alcohol 

1. It burns with a luminous flame. In this it resembles ethyl 
alcohol. In the body however, it is not so readily oxidized. 

2. It dissolves fats, oils, resins, etc. and is extensively used for 
this purpose being a better solvent for these than ethyl alcohol. 
This greater solvent power for lipoids may be the cause of its 
greater toxicity. 

3. It is miscible with water in all proportions, the same as 
ethyl alcohol. 

4. Methyl alcohol may be converted into methyl salicylate 
(oil of Wintergreen) as follows: 

To some sodium salicylate in a test tube, add an equal volume 
of methyl alcohol and concentrated sulphuric acid. Heat gently. 
The odor is that of methyl salicylate; which is an important anti- 
rheumatic remedy. 

.OH /OH 

C 6 h/ + CH 3 OH = C 6 H/ + NaOH 

X COONa X COOCH 3 

Sodiumsalicylate methylalcohol methylsalicylate. 
Oleum betulse (oil of birch) is also methyl salicylate. 



ALCOHOL 19 

5. Methyl alcohol readily yields formaldehyde on oxidation. 
Heat a small copper spiral to redness and drop it quickly into 
a test tube containing two or three drops of methyl alcohol. 
Note the odor of formalin. This same reaction takes place in 
the body when methyl alcohol is taken. 

H H 

H— C— H-> H— C— OH-> H— cf 

I I H 

H H 

Methane Methyl alcohol Formaldehyde 

An oxidation of the hydrocarbons has not been observed in 
the body. 

ETHYL ALCOHOL 

Ethyl alcohol, C2H5OH, grain alcohol, or alcohol, is the next 
higher homologue in the methyl series, and is the result of fer- 
mentation of the sugars, of fruits and certain plants. Sugar 
and consequently alcohol may be prepared from any plant that 
contains starch. The U. S. P. (IX) requires that the ordinary 
commercial alcohol contain not less than 92.3 per cent, by weight 
and 94.9 per cent, by volume of C 2 H 5 OH. When a specific 
kind of alcohol is not mentioned, ethyl alcohol is always 
understood. 

Alcohol dilutum contains alcohol, one-half, and distilled water 
one-half by volume. 

Alcohol dehydratwn or absolute alcohol is obtained by treating 
96 per cent, alcohol with quicklime, and distilling. The lime 
holds all but the last traces of water which are taken out with 
anhydrous copper sulphate. When rectified again, it contains 
0.5 per cent, water in which form it is used commercially, but the 
pure absolute alcohol can be obtained by treating the latter with 
barium oxide and re-distillation. Absolute alcohol is so hygro- 
scopic that as a rule it is not found on the ordinary market. 
It contains 0.5 to 1 per cent, water. To prove the presence of 
water in alcohol, drop a small piece of anhydrous copper sul- 
phate into 5 eo. of alcohol. Shake and let it stand. If the 



20 CHEMICAL PHAKMACOLOGY 

slightest trace of water be present, a light blue color develops. 
Also if a few drops of liquid paraffin be added to the same 
amount of alcohol and shaken, a cloudiness due to the formation 
of an emulsion by the water, indicates the presence of water. 

Whiskey, is prepared from fermented grain, potatoes, or any- 
thing containing starch. The starch is hydrolyzed to glucose and 
this on fermentation yields alcohol. Whiskey contains about 
45 to 55 per cent, alcohol. 

Gin, containing about 40 per cent, alcohol, is also made from 
grain and in its final distillation, juniper berries, anise seed, etc., 
are added. 

Rum, prepared from fermented molasses, contains from 45 to 
55 per cent, alcohol. 

Brandy, prepared from fermented juices of such fruits as 
grapes, apples, peaches, etc. contains about 45 to 55 per cent, of 
alcohol. 

Wine, champagne, and beer, are obtained by direct fermenta- 
tion and are not distilled. Wine and champagne contain about 
8 to 10 per cent, alcohol. 

Beer is produced by fermenting malted grain with the addition 
of hops, for the taste. It contains from 3 to 5 per cent, alcohol. 

Alcohol is important because of : 

1. Its local irritant action. 

2. Its action on the central nervous system. 

3. Its destructive action on the tissues. 

4. Its supposed food value. 

A study of these properties places alcohol among drugs and 
poisons rather than among foods. 

When alcohol over 60 per cent, is applied to the skin it tends 
to unite with the living protoplasm and the reaction produces 
redness, itching and a sense of heat. On mucous membranes 
and especially on abrasions the irritant action is much greater. 
If applied to blood or protein solution, alcohol over 60 per cent, 
will cause precipitation on standing. This union with protein 
confers astringent properties on alcohol. Alcohol, however, 
even in strong solutions (90 per cent.) may be slowly injected 
into the blood stream without causing precipitation, since the 
circulation causes it to be rapidly diluted. On the cerebrum 



ALCOHOL 21 

alcohol depresses progressively the psychic, sensory and motor 
functions. It attacks the brain functions in the reverse order of 
their evolution. The sense of judgment, attention, perception, 
reflection, and logical sequence are first to be depressed. The 
apparent stimulation being due to depression of the controlling 
function. There is no stimulation of the intellectual faculties, 
as shown by psychological tests of accuracy, rapidity, or mental 
exercise. There is no stimulation of the motor areas of the brain 
as shown by response to electrical stimulation of the areas. 
There is no stimulation of the medulla as judged by effect on 
blood pressure, heart and respiration. There is no stimulation 
of the cord as judged from the condition of the reflexes. The 
peripheral nerves and nerve endings are depressed and neuritis 
may be produced by continued use of alcohol. Bacterial toxins 
and heavy metals such as lead and arsenic may cause a similar 
neuritis. 

The destructive action on the tissues is shown by : 

The antiseptic action. The growth of microorganisms is 
retarded by all concentrations over 10 per cent. The greatest 
effect being manifested by about 70 per cent. This is apparently 
due to the fact that stronger solutions cause a precipitation film 
on the surface of the organism which retards absorption. 

The gastro-intestinal tract especially of the stomach of alco- 
holics frequently shows a chronic inflammatory condition. 
Nephritis and hepatitis are very common, and neuritis due to 
alcohol is relatively frequent. 

Alcohol as a food — a great deal can be oxidized in the body and 
to that extent it is a food. A dog weighing 25 lbs. is known to 
have oxidized 95 per cent, of 16 grams absolute alcohol in 5}^ 
hours. It can also replace fat and carbohydrates to a certain 
degree and spare protein waste, but it cannot build up tissue. 
Since it is easily oxidized and can supply energy, and prevent 
tissue destruction, it may be used as a medicinal food. Its 
destructive action on the tissues and its proneness to result in 
the formation of a vicious habit, prevent its being classified with 
foods. 

Offer gives the following experiment on a healthy man to show 
the effects of alcohol, as a food: 



22 



CHEMICAL PHARMACOLOGY 
Gram Nitrogen 



Period 1. 


Diet alone 


Loss, 0.3441 


Body nearly in nitro- 
genous equilibrium 


Period 2. 


Diet 100 grams oi. 


Loss, 1 . 1689 


Toxic action on tis- 




alcohol 




sues 


Period 3. 


Diet 100 grams of 


Gain, 0.2335 


Tolerance beginning 




alcohol 




to be established, 
and alcohol acting as 
a protein-spaiing 
foodstuff 


Period 4. 


Diet alone 


Loss, 0.0110 


• 


Period 5. 


Diet with added fat 
equivalent to 100 
grms. of alcohol 


Gain, 1.5654 





The Fate of Alcohol in the Body. — Alcohol is readily absorbed. 
Even from the stomach from which absorption is usually slight, 
about 20 per cent, of ingested alcohol is absorbed. After ab- 
sorption the greatest amounts are found in the blood and central 
nervous system. When the blood contains 0.12 per cent, there 
is stupor, but as much as 0.72 per cent, has been found in a case of 
fatal intoxication. More than six parts per one-thousand in the 
blood invariably proves fatal. It is said that if stupor or un- 
consciousness after a drinking bout last over 10-12 hours re- 
covery rarely takes place. Traces remain in the blood for 
twenty-four hours, but over 95 per cent, of the amount ingested 
is oxidized. Whether the blood normally contains traces of 
alcohol is a disputed question. Traces have been found in normal 
blood but there is a question whether or not this was formed 
by an abnormal fermentation of carbohydrates in the intestine, 
rather than as a normal product of digestion. 

B. Fischer reports the following analysis of the alcoholic con- 
tent of the organs of a man who died from alcoholic intoxication : 

Weight Organ Alcohol 

2720 grams Stomach and intestines 30 . 6 grams 

2070 grams Blood — heart and lungs 10 . 85 grams 

1820 grams Kidneys and liver 7.8 grams 

L365 grams Brain 4.8 grams 

Ethyl alcohol is recognized by its odor and by chemical tests. 



ALCOHOL TESTS 23 

Since it distils easily from water solution, if it is in dilute solutions, 
as beer, or in colored solutions, as wines, it should be distilled 
before testing. The first part of the distillate should be used for 
the test. 

Chemical Tests for Ethyl Alcohol 

1. To a small portion of the distillate add a crystal of potassium 
bichromate and a few drops of H 2 S0 4 and warm. The alcohol 
is oxidized to the aldehyde and acetic acid with the characteris- 
tic odor, and the chromate is reduced giving a green color. Do 
not use too much bichromate. 

1. K 2 Cr 2 7 + H 2 S0 4 = K 2 S0 4 + H 2 Cr 2 7 (H 2 + 2Cr0 3 ) 

2. 3C 2 H 5 OH + 2Cr0 3 + 3H 2 S0 4 = 3CH 3 CHO + Cr 2 - 

(S0 4 ) 3 + 6H2O ' 

2. Lieben's Iodoform Test. — To a few drops of dilute alcohol 
in a test tube add a crystal of iodine. Warm gently and add 
drop by drop KOH until the red color just disappears. Note 
the odor. When the sediment has settled examine under the 
microscope. 

C 2 H 5 OH + 4I 2 + 6KOH = CHI 3 + HCOOK + 5KI + 6H 2 0. 

Bromoform can be prepared in the same way by using bro- 
mine instead of iodine. Acetone also gives this test but differs 
from alcohol in that it will give it when NH 4 OH is used instead 
ofKOHorNaOH. 

3. Ethyl Acetate Test. — Mix equal volumes of alcohol or the 
liquid to be tested and concentrated sulphuric acid : About 2 cc. 
each. To this add about 0.1 gram dry sodium acetate and heat. 
Ethyl acetate is formed if alcohol is present and is recognized by 
its odor : 

O X>C 2 H 5 

1. C 2 H 5 OH + H 2 S0 4 \$S + H 2 

CT X OH 

2. CH 3 COONa + C 2 H 5 .O.S0 2 OH = CH 3 COOC 2 H 6 + 

NaHS0 4 

There is no evidence that any substance formed in making 
these tests is ever formed from alcohol in the body. 



24 



CHEMICAL PHARMACOLOGY 



To Determine the Amount of Ethyl Alcohol in Liquors 

Place 100 cc. of the liquid in a flask of about 300 cc. capacity. 
Add 50 cc. of water. Connect with a condenser and distil over 
100 cc. This contains all the alcohol in a water solution. De- 
termine the specific gravity of the distillate by means of a pyc- 
nometer, Westphal balance, or a delicate hydrometer. Read 
the per cent, of alcohol from tables prepared for this purpose. 
See U. S. P. IX. page 633. These tables were prepared as fol- 
lows: Water has a specific gravity of 1.0000. Absolute alcohol 
has a specific gravity of 0.79365, consequently between per 
cent, alcohol and 100 per cent, we have a range of sp. gr. of 
0.20635. By mixing known amounts of water and alcohol and 
carefully measuring the sp. gr. of such mixtures, the tables 
were prepared. 

Propyl and Butyl Alcohols 

Propyl and butyl alcohols are not used in medicine and are of 
interest only as impurities in preparations of ethyl alcohol. 
Propyl is more powerful in its action than ethyl and butyl still 
stronger than propyl. The toxic action increases with increas- 
ing molecular weight. This is known as the Rule of Richardson. 
There are two propyl alcohols — the normal and the isopropyl. 



There are Four Butyl Alcohols. C 4 H 9 OH 





B. P. 


Specific gravity at 20° 


CH 3 — CH 2 — CH 2 — CH 2 OH ' 


117° 


.810 


Normal butyl alcohol (primary carbinol) 






(CH 3 ) 2 CH— CH 2 OH 


117° 


.806 


Isobutyl alcohol (primary isopropyl carbinol) 






CH3 ~CH^ CH0H 


100° 


.808 


Normal secondary butyl alcohol (methyl ethyl 






carbinol) 






(CH 3 ) 3 COH 


83° 


.786 


Tertiary butyl alcohol (trimethyl carbinol) 







BUTYL ALCOHOLS 25 

The normal alcohol when oxidized gives propionic aldehyde and 
acid, while oxidation of isopropyl alcohol gives acetone. 

CH 3 — CH 2 — CH 2 OH -h> CH 3 — CH(OH)— CH 3 

Primary propyl alcohol (normal) Secondary propyl alcohol (iso- 
propyl alcohol) 

Normal butyl occurs in traces in fusel oil. It is also produced 
by Bacillus butylicus when grown on glycerine and various 
sugars, but it has little biological importance. The toxicity of 
these and other alcohols on fish has been studied by Picaud who 
gives the relative toxicity as follows: 

Methyl . 66 

Ethyl 1.00 

Propyl 2.00 

Butyl 3.00 

Amyl 10.00 

On the isolated mammalian heart Hemmedter found that the 
pumping power as measured by the amount expelled in 30 sec- 
onds was reduced by the various alcohols as follows: 

Methyl 19 cc. 

Ethyl 17 cc. 

Propyl 7$ cc. 

Butyl 161 cc. 

Amyl 323 cc. 

Isopropyl is more toxic than normal, but normal butyl is 
more toxic than isobutyl. Alcohols with branched chains are 
less toxic than those with straight chains. 

Amyl alcohols: 

Only primary isobutyl carbinol and secondary butyl car- 
binol, are important in pharmacology. Ordinary amyl alcohol 
is a mixture of these. Both occur in fusel oil, and are 
formed through the life processes of the yeast cell and are 
derived from proteins. Consequently where a fermentation 
mash contains proteins, as when grain and potatoes are used, 
more amyl alcohol is produced, than in the preparation of rum 
or brandy where the mash contains less protein. Yeast may 



26 



CHEMICAL PHARMACOLOGY 



Amyl Alcohol or Pentyl Alcohol 

(Amylum-starch) 
There are Eight Amyl Alcohols 









Specific 






B. P. 


gravity at 
20° 


1. Normal primary (butyl carbi- 








nol 


CHs— CH2— CHr- CH2— CH 2 OH 


138° 


.817 


2. Isobutyl carbinol (primary) 


CH 3 \ 

>CH— CH2— CH2OH 
CH/ 








130° 


.810 


3. Secondary butyl carbinol (pri- 


CHsv 

)>CH— CH 2 OH 
CH3— CH 2 X 






mary) (active amyl alcohol). . 


128° 


.816 








4. Tertiary butyl carbinol (pri- 


CH 3 \ 

CH 3 ^C— CH2OH 

CH 3 / 






mary) 


113° 








5. Methyl propyl carbinol (secon- 


CH 3 \ 

^CHOH 






dary) 


119° 










b\ Methyl isopropyl carbinol (sec- 


CH 3 \ 






ondary) 


CHsv >CHOH 
CHjf 


112° 


.819 


7. Diethyl carbinol 


CHs-CHa 

yCHOH 
CH3— CHi^ 








117° 










8. Dimethyl ethyl carbinol (ter- 


CH 3 \ 

CH 3 ~C— OH 
CH 3 — CH/ 






tiary) 


102° 









produce amyl alcohol from its own protein consequently, all 
yeast alcohols may contain amyl alcohol. The specific constit- 
uent of the protein from which- amyl alcohol is prepared appears 
to be leucine and isoleucine. Ehrlich, using a pure culture of 
yeast, found that when this acted on a sugar solution contain- 
ing leucine it readily yielded isoamyl alcohol and isoleucine 
yielded amyl alcohol. The reactions are represented as follows: 

(1) (CH 3 ) 2 .CH.CH 2 CH(NH 2 ).COOH+ H 2 = (CH 3 ) 2 .CH. 

CH 2 CH 2 .OH + C0 2 + NH 3 
Leucine Isoamyl alcohol 

(2) CH 3 .CH(C 2 H 6 ).CH.(NH 2 ).COOH + H 2 = CH 3 .CH(C 2 H 5 . 

CH 2 OH + C0 2 + NH 3 
Isoleucine d-amyl alcohol 

The amyl alcohols arc colorless oily liquids insoluble in water, 



AMYL ALCOHOL 27 

with a disagreeable characteristic odor and acrid taste. Their 
action in general resembles ethyl alcohol but they are about four 
times as toxic. They are more locally irritant, and some authori- 
ties state that the effect of chronic use is more deleterious than 
in the case of pure ethyl alcohol. 

Fusel oil is to some extent used in the preparation of essences 
and perfumes, and exerts an influence on other perfumes. The 
essential oils and aromatic substances develop their finest odors 
in alcohol from a special source. In some cases such alcohols are 
treated with charcoal which removes most of the fusel oil, the 
remaining traces act with other aromatic bodies to produce a 
harmony which cannot be reached by any other alcohol. Ehr- 
lich points out that "the great variety of the bouquets of wine 
and aromas of brandy, cognac, arrak, rum, etc. may be very 
simply referred to the manifold variety of the proteins of the raw 
materials (grapes, corn, rice, sugar cane, etc.) from which they 
are derived." 

When oxidized, amyl alcohol is converted into valerianic acid 

(CH 8 ) a CH.CH 2 COOH 

which may be recognized by its odor. 

TESTS 

1. To test ordinary alcohol for fusel oil constituents: Mix 
10 cc. of alcohol with 5 cc. of water and 1 cc. of glycerine and 
allow the mixture to evaporate spontaneously from a piece of 
filter paper. No odor should be perceptible when the last traces 
of alcohol leave the paper. Compare this with a similar solution 
to -which 1 cc. of amyl alcohol has been added. 

2. Warm 1 cc. of amyl alcohol with 2 cc. of concentrated 
H 2 S0 4 . A rose red color is produced. 

3. Heat 1 cc. of amyl alcohol with 1 cc. H 2 S0 4 and a little 
sodium acetate. Amyl acetate is produced which has a strong 
smell of pears and is known as pear oil. 

4. Heat 1 cc. of amyl alcohol with 1 cc. H 2 S0 4 and a 
small crystal of potassium bichromate; valerianic aldehyde 

CH 3 (CH 2 ) 3 <X is formed. This has a peculiar characteristic 

X H 
odor. 



28 CHEMICAL PHARMACOLOGY 

Valeric or valerianic acid (CH 3 (CH 2 )3COOH) is the acid cor- 
responding to amyl alcohol, just as acetic is the acid of ethyl 
alcohol. There are four possible isomerides of valeric acid. 
The normal vaLeric acid is N. propyl-acetic acid CH 3 CH 2 CH 2 . 
CH2.COOH. 

Valerian, which is used in medicine in cases of hysteria and 
other functional nervous trouble contains valerianic acid as the 
active or odoriferous principle. The action in these cases is 
psychic, and due to the impression made by the odor. 

DIHYDRIC ALCOHOLS 

These are of no pharmacologic interest except in illustrating 
the influence of the change of the molecule on its physical and 
physiological actions. The only dihydric alcohol that is used 
at all is glycol or ethylene glycol, 

CH 2 OH 

I 
CH 2 OH 

Do not confuse this with glycocoll (p. 67) . The two hydrox- 
yls here render the substance more soluble in water and less 
soluble in other liquids, hence lessen the physiological activity 
(See Meyer and Overton theory of narcosis). The introduction 
of OH groups in this series also increases the sweetness of the 
substance. Glycerine contains three OH groups and glucose five, 
and they are sweeter in about this proportion. This is still more 
strongly emphasized under trihydric or triatomic alcohol- 
glycerine. 

Glycerine, which contains three hydroxyl groups is still less 
active, and glucose, which is an hexatomic alcohol, is not toxic. 
In fact, sugars are classified as foods rather than drugs. 

Ethylene glycol is a thick, colorless, syrupy liquid with a 
sweet taste (Greek, "glykys" meaning, sweet, and "ol, " 
alcohol). It boils at 197.5° and mixes with water and alcohol 
in all proportions. It was formerly recommended in the treat- 
ment of tuberculosis, but is now considered worthless for this 
purpose. 

Glycol is formed when choline is heated: 



GLYCOL 29 

CH 3 CH 2 .CH 2 OH CH 3x 

CH3— N— OH > CH 3 — )N + CH 2 OH 

CH 3 CH/ CH 2 OH 

Choline Tri-methylamine. Glycol 

Nitric acid oxidizes glycol to oxalic acid : 

CH 2 OH CHO CHO COOH 

CH 2 OH CH 2 OH CHO COOH 

Glycol glycolaldehyde glyoxal oxalic acid 

These products are formed when glycol is oxidized in the body. 
Oxalic acid is also formed from cellulose on treatment with caustic 
potash, but it is doubtful if any such action occurs in the animal 
body. 

Glycolaldehyde is one of the products of the oxidation of 
dextrose with alkalies and is thought by some to be formed in 
the oxidation of sugars in the body. 

TRIHYDRIC ALCOHOLS 

-Of trihydric or triatomic alcohols, glycerine only is important. 
It is used extensively in medicine. 

CH 2 OH 
CHOH 

CH 2 OH 

It has a strong avidity for water, and because of this when applied 
to mucous membranes it is irritating. All ordinary fats are 
esters of glycerine and a fatty acid. Glycerine is sweeter than 
glycol and is the only trihydric alcohol found in nature. 

Chemical Tests 

• 

1. Test the solubility of glycerine in water, alcohol, and ether. 
The increase in hydroxyl groups, as a rule, decreases the solu- 
bility in ether, and increases the solubility in water. Compare 
this with other alcohols. 



30 CHEMICAL PHARMACOLOGY 

2. Taste alcohol, glycol, glycerine, and glucose. The hexoses 
are alcoholic compounds. Increasing the hydroxyl groups is in 
some way connected with the sweet taste, though not absolutely 
essential to the taste, for benzosulphinidum, lead acetate, etc. 
which have no (OH) groups may be five hundred times sweeter 
than sugar (see p. 210). 

3. Heat a few drops of glycerine with a small crystal of KHS0 4 
over a free flame. It is dehydrated with the formation of acro- 
lein ("Acer," acrid, and " oleum," oil). 

C 3 Hb(OH) 8 = C 3 H 4 + 2H 2 or C 3 H 5 (OH) 3 = CH 2 : CH.CHO 

+ 2H 2 

Glycerine is used to a considerable degree in medicine. It 
was formerly recommended in the treatment of diabetes, as a 
sweetening agent to replace sugar. It has been found, however, 
to be of little use in these cases. In larger doses (5-20 cc.) it 
is a laxative, but may produce gastro-enteritis. It is used in 
suppositories as rectal enemata in cases of constipation; as a 
vehicle or solvent for many drugs, and especially in the glycerites 
of tannic acid, starch, and boroglycerine. It has some power as 
a germicide, and is used to preserve vaccine lymph. The use of 
it in skin diseases combined with substances like benzoin, for 
chapped hands, lips, or other parts is common. It has many 
other uses in medicine. 

HIGHER ALCOHOLS 

Cetyl alcohol, Ci 6 H 33 OH, is found in spermaceti, and myricyl 
alcohol, C 30 H 6 iOH, in waxes. These alcohols in waxes corre- 
spond to the glycerine of ordinary fats; this is the main differ- 
ence between the fats and waxes (q.v.). In waxes the fatty acid 
also is higher in the series (more C atoms) than the palmitic, 
stearic or oleic acids of the ordinary fats. 

SULPHUR ALCOHOLS OR MERCAPTANS 

The sulphur alcohols correspond to the ordinary alcohols in 
which (S) takes the place of (0). Ethyl mercaptan is formed 
from ethyl chloride and potassium sulphydrate in alcohol solu- 
bion: C2H5CI + KSH - C 2 H 5 SH + KC1 

The sulphur confers greater chemical reactivity and also greater 



GENERAL ACTION OF ALCOHOLS 31 

pharmacological activity on the alcohols. While the OH in 
ordinary alcohols is replaceable only with Na, or K, the mercap- 
tans react also with heavy metals. The name comes from their 
reaction with mercury (mercurium captans) : 

2C 2 H 5 .SH + HgO = (C 2 H 5 S) 2 .Hg + H 2 
The sulphur alcohols are not used directly in medicine, but are 
used in the manufacture of some medicinal agents. Ethyl mer- 
captan is important because it was the first discovered mercaptan, 
and because it forms the basis for the manufacture of the sul- 
phone group of hypnotics, of which sulphonal or sulphonmethane 
is the most important. 

THE PHARMACOLOGY OF THE ALCOHOLS IN RELATION TO 
THEIR CHEMISTRY 

The relative inertness of the paraffins is markedly activated 
by the introduction of the OH groups. The monhydric alco- 
hols are pronounced narcotics, which action, seems to depend 
on the hydrocarbon radical. Thus, CH 4 is inert, CH 3 OH, nar- 
cotic. Further oxidation destroys the CH 3 groups, and the nar- 
cotic action is lost. Ethane CH3CH3 is inert, ethyl alcohol 
CH 3 CH 2 OH is narcotic, while if both CH 3 groups in ethane are 
oxidized giving glycol, CH 2 OHCH 2 OH, it is inactive. All 
hydrocarbons are relatively inert except those that are volatile 
liquids and have a solvent action. 

Propyl alcohol, CH 3 CH 2 CH 2 OH, is more toxic than ethyl, 
but when two more OH groups are substituted for H, as in 
glycerol, CH 2 OH.CH.OHCH 2 OH, it loses its soporific and toxic 
action. In large doses it may produce restlessness, tremors, and 
even tetanus. These actions, however, are less than those of 
propyl alcohol, and are apparently more on the motor than on 
the sensory side of the nervous system. 

As the number of carbon atoms in alcohols increases, the toxic- 
ity increases. The six carbon alcohols or aldehydes correspond- 
ing to the hexanes are highly toxic, while the corresponding 
sugars are foods. Thus, normal hexane CH 3 CH 2 CH 2 CH 2 CH 3 
is actively intoxicant, producing excitement followed by deep 
anesthesia when inhaled. Glucose, CH 2 OH (CHOH) 4 CHO, has 
no toxic properties in any amount. Secondary alcohols are 
more toxic than primary, and tertiary more than secondary. 



32 CHEMICAL PHARMACOLOGY 

The action of the alkyl radical of the alcohol is especially 
noticeable in the tertiary alcohols where it is found that the 
larger the alkyl radical attached to the carbon carrying the 
hydroxyl, the more pronounced is the action, e.g., 

4 grams of tri-methyl carbinol (tertiary butyl alcohol) 

(CH 3 ) 3 COH, or 
2 grams of dimethyl ethyl carbinol (CH 3 )2. 

V)OH, or 
C 2 H 5 
1 gram of tri-ethyl carbinol (C 2 H5) 3 COH have about the 
same sleep-producing power. A similar characteristic has been 
observed in other compounds. 
CH 2 OH 
Glycol, I the dihydric primary alcohol, is inert, but if 

CH 2 OH 
alkyl groups are introduced, in place of the hydrogen attached 
to the carbon, substances known as pinacones are formed (Gr. 
pinax, pinak tablet) . It has been found that 10 grams of methyl 
pinacone 

(CH 3 ) 2 COH ' ■ . (C 2 H 5 ) 2 COH 

(CH 3 ) 2 COH ° r L5 gmmS ° f ethyl pmaC ° ne ' (C 2 H 6 ) 2 COH 

have about the same sleep-producing or depressing action. 

These examples show clearly the pharmacological action of 
alkyl radicals, which are hypnotics or depressants of the central 
nervous system, and the greater the molecular weight the greater 
the depression produced. 

IV. ANESTHETICS, NARCOTICS, SOPORIFICS, 
HYPNOTICS 

The alkyl radicles are nerve depressants, and affect the cere- 
brum especially. According to the degree of depression pro- 
duced, several terms are used to define the condition. 

Hypnotics, soporifics or somnifacients are used to produce 
sleep. Alcohol, ether, or chloroform, in the proper dose may be 
used, but more often milder bodies such as chloral, paraldehyde, 
the sulphones, veronal, or similar drugs are used. 

Narcotics produce a condition of narcosis or coma. The 
depressant action is more profound than the hypnotic state and 



ANESTHESIA 



33 



may be produced by larger amounts of the same drugs. In 
addition to the aliphatic narcotics mentioned, urethane and 
morphine readily produce narcosis. The aliphatic anesthetics 
most used are ether, ethyl chloride, and chloroform. Nitrous 
oxide, although not an aliphatic preparation is usually studied 
with them. The action of each of these is practically the same 
as alcohol, but the stages of the action are more prolonged in 
alcohol intoxication. Some stages in general anesthesia pro- 
duced by ether or chloroform may be so fleeting that they are 
difficult to observe. 

Four distinct stages may be observed following the administra- 
tion of the aliphatic narcotics and hypnotics. 

Dixon gives the stages with the symptoms of ether anesthesia 
as follows : 



Stage I. 



Disorganized 

consciousness 

and 

analgesia 



Stage 2. 



Excitement 
and 

Unconscious- 
ness 



Irritant action of the vapour on the nasal and 

bronchial mucous membrane. 
Reflex effects — coughing, salivation, respiratory, 

cardiac. 
Disturbances of judgment. 
Loss of memory and self-control. 
Emotional tendencies. 
Disturbances of special senses. 
Analgesia. 
Vertigo and ataxia. 

Quickened pulse and rise in blood-pressure. 
Increased respiration. 
Dilated pupils. 



Coughing, retching, vomiting. 

Delirium varying from shouting to inarticulate 

muttering. 
Tonic, and clonic muscular spasm. 
Reflexes diminished. 
Unconsciousness. 

Respiration irregular from the struggling. 
Pulse accelerated and pupil dilated, both from 

excitement. 



34 



CHEMICAL PHARMACOLOGY 



Stage 3. 



Surgical 
Anesthesia 



Stage 4. 



Leading to 
Bulbar para- 
lysis 



Muscular relaxation. 

Loss of reflexes. 

Breathing regular, often "snoring." 

Decrease of respiratory exchange. 

Fall of temperature. 

Fall of blood pressure. 

Pupil small; does not react to light. 

Loss of bladder and rectal reflexes. 

Paralysis of vaso-motor centre (great fall of 

blood-pressure) . 
Paralysis of respiratory centre. 
Widely dilated pupils. 
"Great depression of cardiac muscle. 



The amount of chloroform in the blood during light anesthesia 
is 25 to 35 mgs. per 100 cc. If the concentration is raised to 40-70 
mgs. per 100 cc. respiration fails. During light ether anesthesia 
there are 100-110 mgs. per 100 cc, and 130 to 140 mgs. in deep 
anesthesia.. 160 to 170 mgs. per 100 cc. causes failure of respira- 
tion. In deep alcoholic coma in man Sweisheimer found that 
the blood contained 2.25 parts per 1000 cc. Grehant found that 
6 parts alcohol per 1000 cc. blood was invariably fatal to 
animals. 

Whether the heart or respiration stops first depends on the 
method of administration. Large concentrations especially of 
chlorine containing anesthetics, if too quickly administered, 
paralyze the heart before respiration. When present in the 
respired air, in the per cent, given, Cushny tabulates the differ- 
ences between ether and chloroform as follows: 

Chloroform Ether 

0.5-0.7 per cent. 1.5-2.5 per cent. - Insufficient to cause anes- 
thesia. 

1.0 per cent. 3-3.5 per cent. Causes anesthesia on pro- 

longed inhalation. 

2.0 per cent. 6.0 per- cent. Arrests respiration after 

sometime. 



ANESTHETICS 



35 



The amount of anesthetic in 100 cc. of the blood shows the same 
proportion and is as follows: 

Chloroform Ether 

25-35 mgs. 100-140 mgs. 

40-70 mgs. 160-170 mgs. 

According to the concentration of chloroform in the respired air, 
Rosenfeld gives the following series of experiments to show the 
effects : 



Anesthesia 
Respiratory arrest. 



Relationship Between the Percentage of Chloroform in the Re- 
spired Air and the Depth and Rapidity of the Anesthesia (Rosenfeld, 

Spenzer) 
(From Meyer & Gottlieb) 



Chloroform 


Time necessary 


Depth of 




percentage in 


to induce 


anesthesia or 


Remarks 


respired air 


anesthesia 


narcosis 




0.54-0.69 


2 hrs. 


No narcosis 


Somnolence only. 


0.96-1.01 


30-40 min. 


Complete 


Blood-pressure at first nor- 
mal then gradual fall for 
4 hrs. Respiration nor- 
mal. 


1.16-1.22 


30 min. 


Complete 


Cessation of respiiation at 
end of 2 hrs. 


1.41-1.47 


37 min. 


Deep 


As above after 1 hr. 


1.63-1.65 


12 min. 


Deep 


As above after 30 min. 


Ether 








percentage in 








respired air 








1.5 


2 hrs. 


Hardly any 


Slight somnolence only. 


2.5 




Very incom- 
plete 


Reflexes maintained. 


3.2-3.6 


25 min. 


Complete 


Respiration and cardiac 
function remained good 
for hours. 


4.45 


15 min. 


Complete 


Respiration slow and regu- 
lar; pulse accelerated. 


6.0 






Respiration ceased in 8- 
10 minutes. 



36 CHEMICAL PHARMACOLOGY 

THEORIES REGARDING THE CAUSATION OF ANESTHESIA 

Both chemical and physical theories have been advanced 
to explain the action of ether and chloroform in producing 
anesthesia. 

1. The Meyer-Overton Theory. — Meyer and Overton think 
that anesthesia is due to the solvent action of the anesthetic on 
the lipoids of the central nervous system. The anesthetics are 
also somewhat soluble in water, and the anesthetic value depends 
on the distribution, coefficient, i.e. the ratio of the solubility 
in fats (S/F) to the solubility in water (S/W). The most power- 
ful anesthetics are very soluble in fats and but little soluble in 
water. Meyer studied many aliphatic narcotics and arranged 
them in the order of their potency. These are expressed in the 
fractions of normal solutions, that will produce the first definite 
physiological effect, which he calls the liminal value. 

Liminal value in Distribution SF 

terms of normal „, _. . . ^= 

solution Coefficient SW 

Trional 0.0018 4.46 

Tetronal 0.0013 4.04 

Sulphonal 0.006 1.11 

Butylchloral hydrate 0.002 1.59 

Bromal hydrate 0.002 0.66 

Chloral hydrate 0.02 0.22 

Ethyl methane 0.04 0. 14 

Methyl methane ,....' 0.4 0.04 

Monacetin 0.05 0.06 

Diacetin 0.015 0.23 

Triacetin 0.01 0.3 

Chloralamide 0.04 

Chlorhydrin 0.04 

Dichlorhydrin 0.002 

While this theory is attractive, it merely explains how the 
drug gets to the piace of action, and Cushny has pointed out 
that some benzene derivatives are good lipoid solvents and have a 
high distribution coefficient, yet are without narcotic action. 
Again cells rich in lipoid substances are not always attacked in 
relation to this substance. The peripheral nerves are much less 



ANESTHESIA 37 

influenced than the central nervous system. Baumann and Kast 
give the following table to show that narcotic action depends 
on the presence of ethyl radicals. 

Action Distribution 
Coefficient 

Dimethyl-sulpho-methane very slight . 106 

Dimethyl-sulpho-ethane slight .151 

Sulphonal (Diethyl sulphone dimethyl methane) marked 1.115 
Trional (Diethyl sulphone methyl ethyl methane) 

more marked 4.46 
Tetronal (Diethyl sulphone diethyl methane) more marked 4 . 04 

2. The Theory of Moore and Roaf. — They believe that the 
action of the anesthetic is duejtp a loose combination of the anes- 
th etic with the cell proteins. A certain concentration of the 
anesthetic in the blood is necessary to maintain the combination. 
Lipoids may aid in keeping the necessary concentration of the 
anesthetic around the living protein, and to this extent the 
Meyer-Overton theory may hold. 

3. Verworn's Theory. — He accepts the Meyer-Overton theory 
to some extent, but believes that the fundamental action is the 
prevention of oxidation by the cell. In the last step anesthesia 
is an asphyxiation. Due to the presence of the anesthetic the 
nerve cells cannot utilize the oxygen that may be present. 

Many other theories have been presented but none are entirely 
satisfactory. In this connection it should be mentioned that 
physiologists have been unable to present a satisfactory theory 
to explain natural sleep. 

The Hyderabad Commission— 1889 and 1890 

Because of the difficulty of handling ether in hot climates 
such as India, the Nizam of Hyderabad caused an investigation 
to be made of the relative values of ether and chloroform as 
anesthetics, especially with reference to the action on the heart. 
The commission concluded after numerous experiments that 
the only means by which the heart's safety is jeopardized is 
through paralysis of respiration. Accordingly respiration always 
stops first. This report is both right and wrong. According to 



38 



CHEMICAL PHARMACOLOGY 



the conditions of their experiments, where the anesthetic in 
the respired air is dilute and gradually increased, respiration 
stops first. If, however, the concentration in the respired air 
is too great at the beginning, or is quickly increased, the heart 
may stop first due to direct action on and paralysis of the heart 
muscle. It is quite possible, therefore, to have either respiration 
or heart stop first, or both at the same time. Consequently, 
therefore, in giving an anesthetic, it is necessary to watch both 
heart and respiration. 

The relative toxicity of ether and chloroform on the heart 
was found by perfusing the isolated heart through the coronary 
vessels. To stop the heart's action 0.015 per cent, chloroform 
or 0.4 per cent, of ether was required. This indicates that 
chloroform is about 25 times as toxic as ether. On the respira- 
tory center chloroform is about 4 times as toxic as ether. 

Ether and chloroform are excreted mainly by the lungs. Ether 
is excreted only in this way. Small amounts of chloroform have 
been found in the urine and milk, but the statement that some 
carbon monoxide is formed from chloroform in the body is 
erroneous. Chloroform may be detected in the breath for 24 
hours after narcosis. Nicloux gives the following figures to show 
the disappearance from the blood. 



Chloroform Content of Blood after Termination of Anesthesia 



Time elapsed since 


termination of anesthesia 


Per cent, of chloro- 
form in blood 




Exp. 1 


Exp. 2 


minutes 


0.054 
0.0255 
. 0205 
0.018 
0.0135 


. 0595 


5 minutes 




15 minutes 




30 minutes 


0.023 


1 hour 


0.018 


3 hours 


0.0075 


7 hours 


0.0015 







Ether is eliminated somewhat more rapidly, which explains 
the more rapid recovery from ether narcosis. 



ETHER ANESTHESIA 39 

Ether Content op Blood after Termination op Anesthesia 





Per cent, of ether 
in blood 




Exp. 1 


Exp. 2 


minutes 


0.115 
0.071 
0.063 
0.052 
0.025 


0.159 


3 minutes 


0.108 


5 minutes 


0.080 


15 minutes 


0.058 


1 hour 


0.021 


2 hours. 


0.004 







ETHER OR ETHYL OXIDE 

Ether is prepared by mixing alcohol and sulphuric acid and 
distilling. The following formula indicates the reaction. 

EL C 2 BL 

c 2 H 5 0H + y$o 4 = ^so 4 + h 2 o 

W H X 



H CJL 



C 2 H 5 OH + C 2 H 6 < 



\ c 



>0 + H 2 SCX 



SO4 C 2 H5 
Ether used for anesthesia is chemically pure ethyl ether. 

CHEMICAL TESTS 

1. Specific gravity 0.713 to 0.716 at 25°C. Boils at 35°C. 
which is below body temperature (37°C.) 

To show inflammability of ether apply a flame to 1 cc. of it in 
a small dish. Repeat this with chloroform. 

2. Shake ether with an equal volume of CS 2 . The mixture 
becomes turbid if the ether contains water, not otherwise. Ether 
will dissolve about 10 per cent, water. Anilin violet colors ether 
which is adulterated with alcohol, but does not the pure ether. 

3. Shaken with }{q volume of 5 per cent. KOH, no color 
should be developed in either liquid in the absence of aldehyde. 

4. Ether is miscible with alcohol, benzine, chloroform, benzene, 
fixed and volatile oils, and lipoids in all proportions. Test the 



40 CHEMICAL PHARMACOLOGY 

solubility of oils, fats, lanolin, and other lipoids in ether. Cf. the 
Overton-Meyer theory of Narcosis, p. 36. 

5. Na will not act on dry ether due to the absence of hydroxy 1. 

6. Strong acids decompose ether with the formation of ethereal 
salts. The action of H 2 S0 4 on alcohol is much more complete. 
Similarly in the body, ether is excreted unchanged, while alcohol 
is almost completely oxidized. 

The replacement of the hydrogen hydroxyl in alcohol results 
in marked physical and chemical changes. C2H5OC2H5 is much 
more volatile than C 2 H 5 OH. The more volatile a substance the 
more quickly it penetrates, consequently it acts more quickly 
when taken, into the body. 

In the body, alcohol is rapidly and almost completely oxidized. 
Ether is not oxidized in the body, but is a catalytic poison, i.e., 
it causes a marked reaction by action in the body without itself 
undergoing any change. When oxidized outside the body it 
yields the same products as alcohol. Ethers of the marsh-gas 
series are always more active than the corresponding alcohol. 

CH 2 OH 
Glycerine — CHOH is inert, but when converted into glycerine 

CH2OH 
ether 
CH 2 — 0— CH 2 
CH — 0— CH 
CH 2 — 0— CH 2 

it becomes narcotic. The narcotic action of the alkyl radical 
is manifested in other compounds. Phenol CeEUOH which is 
antiseptic and stimulating to the motor side of the cord loses its 
antiseptic and stimulating action when converted into phene- 
tol, C 6 H 6 .O.C 2 H 5 . 

NH 3 , which is stimulating, loses its convulsant action as the 
hydrogen atoms are replaced by alkyls and the quaternary 
ammonium bases have a curara-like action. 

Urea also becomes depressant when alkyl groups are sub- 

y NH 2 /N(C 2 H 5 ) 2 



stituted for H, as when CO<f becomes C0< 

X NH 2 X NH(C 2 H 5 ) 

These examples again show the depressant and hypnotic action 
of the alkyl groups. 



HYPNOTICS 41 

ETHYL CHLORIDE 

Ethyl chloride, C 2 H5C1, is prepared bypassing HC1 gas through 
alcohol in which anhydrous ZnCl 2 is dissolved, the ZnCl 2 acting 
as a catalytic and dehydrating agent. At ordinary temperatures 
it is a gas which boils at 12.5°C. It is freed from HC1 by passiog 
through water. 

This compound, like chloroform, illustrates the influence of 
introducing CI into the molecule. It is twice as soluble in water 
as in the blood, and is sometimes used as a general anesthetic, 
especially in nose and throat work. It has a greater paralytic 
action on the heart muscle than ether, but much less than chloro- 
form. All anesthetics containing chlorine act strongly on the 
heart, as depressants. 

Its main use is as a local anesthetic, the action being due to its 
rapid evaporation. Freezing with any other agent would have 
the same effect. 

The most prominent action of the methane group as a whole 
is the anesthetic, hypnotic, and analgesic action. The members 
of the benzene series on the other hand have a more pronounced 
action on the motor side of the nervous system and are antiseptics. 

HYPNOTICS AND ANALGESICS OF THE METHANE SERIES 

(Hypnos — sleep) (An. without — algos — pain) 
These may be divided into: 

1. The chloroform group 

2. The urethane group 

3. The sulphone group 

1. The Chloroform Groups — Chloroform, CHC1 3 , is formed by 
the action of bleaching powder (a mixture of CaCl 2 and CaOCl 2 ) 
on dilute alcohol or acetone. The chloroform is distilled off, 
washed, and treated with concentrated H 2 S0 4 to destroy other 
derivatives, and is then rectified. The bleaching powder supplies 
chlorine which is an oxidizing agent. 

The reactions are complex, and probably as follows : 

1. C 2 H 5 OH + CaOCl 2 = CaCl 2 + CH 3 CHO + H 2 

2. 2CH3CHO + 6CaOCl 2 = 3CaCl 2 + 3Ca(OH) 2 + 2C 2 - 

HCI3O 

3. 2C 2 HC1 3 + Ca(OH) 2 = 2CHC1 3 + Ca(CHO) 2 



42 CHEMICAL PHARMACOLOGY 

CH 3 
4. with acetone: ">CO + 6CaOCl 2 = 2CHC1 3 + 

CH/ 

2Ca(OH 2 ) + Ca(C 2 H 3 2 ) 2 + CaCl 2 

Chemical Tests 

1. Place 2 cc. of chloroform in a dish and apply flame. Com- 
pare with ether and alcohol. 

2. Add a few drops of AgN0 3 to chloroform. No precipitate 
if pure. Why? It contains chlorine. Make alkaline and again 
heat. Compare with chloral. 

3. Evaporate 10 cc. from filter paper on a clean glass slide. 
No odor or residue should remain, if pure. 

4. A paper dipped in chloroform burns with a green mantle 
and HC1 is given off. 

5. Test a few cc. of chloroform by boiling with a few drops of 
KOH and 0.1 gram of resorcinol. The intense red color is due to 
rosolic acid, a derivative of anilin. Chloral gives this same result. 

Resorcinol C 6 H 4 (OH) 2 1:3 /CH 3 

CfiH; 






Rosolic acid C — C 6 H 4 OH 

\ 

C 6 H 4 = O 

In the presence of air, chloroform decomposes slowly into car- 
bonyl chloride (phosgene) and HC1. 

CHC1 3 + O = COCl 2 + HC1. 

The carbonyl chloride is very poisonous. To prevent decom- 
position, it should be kept in the dark; and 1 per cent, alcohol 
added as a preservative. The action of the alcohol is as follows: 

.OC 2 H5 (ethyl carbonate) 
COCl 2 + 2C 2 H 5 OH = CO<( 

X OC 2 H 5 + 2HC1 

6. Chloroform is decomposed by passing its vapor through a 
hot tube. HC1 is formed which can be recognized by testing 
with moist litmus paper, and by the precipitation of AgCl when 
passed into silver nitrate solution. 



THE URETHANE GROUP 43 

7. Phenyl Isocyanide Test. — Add 1-2 drops of aniline and a 
few drops of aqueous KOH to the chloroform. Heat gently. 
Phenyl isocyanide is produced. This has a characteristic in- 
describable repulsive odor. The reaction is: 

CHCI3 + C 6 H 5 NH 2 + 3KOH = C 6 H 5 NC + 3KC1 + 3H 2 

Chloral, chloralhydrate, bromoform, iodoform, and carbon tetra- 
chloride also give this test. The test is sensitive 1 : 6000. 

8. Chloroform will reduce Fehling's solution. 

THE URETHANE GROUP OF HYPNOTICS 

y NH 2 

Urethane: Ethyl carbamate CO<^ 

X OC 2 H 5 

Urea and alcohol under proper conditions yield urethane. — 
/NHo NH 2 

CO\ + C 2 H 5 OH->CO<^ 

X NH 2 OC 2 H 5 + NH 3 

This is soluble in water, a weak hypnotic, and breaks down in 
the body to its components, probably by the following mechanism: 

y NH 2 NH 2 

CO<^ + NH 3 = C 2 H 5 OH + CO<^ 

X OC 2 H 5 NH 2 

Nearly all substances in the body break down much more 
readily into their components than they can be synthesized. In 
the formation of urethane, indirect processes must be employed : 

CI 
CO + 2C1 in sunlight->CO<^ carbonyl chloride 

X C1 
CI CI 

CO/ + C.HsOH-^CO^ + HC1. 

CI OC 2 H 5 chloroformic ester 

/CI /NH 2 

CO<( + NH 3 -^CO<( Urethane + HC1 

X OC 2 H 5 X OC 2 H 5 

It has been found that the pharmacologic action of the ure- 
thanes, like the alcohols, increases with increased molecular 
weight, and with the size of number of the alcohol radicals, con- 



44 CHEMICAL PHARMACOLOGY 

/ OC 2 H 5 

sequently, diurethane, CO<f is a more powerful narcotic, 

X OC 2 H 5 
than urethane. 

,NH 2 
Hedonal, CO<^ ,CH 3 which is the ester of 

C3H7 

urea and the amyl alcohol methyl propyl carbinol, is more power- 
ful than urethane. On account of both the urea and alcohol 
content, these drugs are strongly diuretic. 

VERONAL 

Diethyl malonyl urea, is made from urea, alcohol and malonic 
acid, by the introduction of esters of diethyl malonic acid with 
urea in the presence of metallic alcoholates. The following 
formulse show the principles involved in the formation of veronal, 
and the basis for its chemical name: 



y NH 2 ,NH 2 /)C 2 H 5 
CO<( CO<( CO<( 

X NH 2 X OC 2 H 5 X OC 2 H fi 




+ NH 3 ^ 




Urea Urethane ethyl 




carbonate 


,NH 2 
CO<( + C 2 H 5 OH 
X OC 2 H 5 








urethane alcohol 




or ethyl 




carbamate 




H 


,COOH C 2 H 5x /COOH 


HN 


X COOH C 2 H 6 / X COOH 


^>C = -> 

H 

urea 


Malonic acid Diethyl malonic acid 


C2H5. CONR 

}C/ VlO + 2H 2 
C 2 H, X CONIT 


Veronal 


diethyl malonyl urea 



SULPHONE GROUP 45 

Chemical Tests 

1. Prolonged boiling with sodium carbonate liberates NH3. 

2. In a solution acidulated with HN0 3 Millon's reagent pro- 
duces a precipitate soluble in excess of the reagent. 

3. The melting point of the crystals is 187°-188°C. 

4. The presence of N is shown by fusing with KOH or NaOH 
and making the Prussian blue test, p. 8. 

THE SULPHONE GROUP OF HYPNOTICS 
.OH 

Sulphuric acid may be written /$\ • The replaceable 

(/ X OH 
hydrogen is not directly attached to the sulphur. When salts 
are formed, the replacing metal or radical is also not directly at- 

O / 0— R 
tached to the S ; but to the oxygen : \ S^ 

X 0— R 

Similarly, in ethyl sulphuric 2 S<f 

X OC 2 H 5 
.OCeBU 
or phenyl sulphuric 2 S<^ (combined or etheral 

X OC 6 H 5 
sulphates), the radical is ^ not attached directly to the sulphur 
atom. These bodies are inert and phenyl sulphuric acid occurs 
normally in the urine up to 0.6 grams per day. 

Sulphonic acids are compounds in which the carbon of the 
organic radical present is in direct union with the sulphur; the 
relation between ethyl sulphuric acid and ethyl sulphonic acid 
is shown by the formulae : 

C 2 H 6 O x ,0 CsH. ,0 CH3C ^ 2 ,0 
X >< or >< 

H(/ X H0 X X CH3C h 2 

ethyl sul- ethyl sulphonic acid 

phuric acid 
Where both OH groups of the sulphuric acid are replaced by 

R 
radicals, the product is a sulphone: >S0 2 

R X 



46 CHEMICAL PHARMACOLOGY 

The replaced radical may be methyl, ethyl, or any other alkyl 
group. 

SULPHONAL 

When acetone is mixed with mercaptan in the presence of 
HC1 they condense: 

CH3K CH.3v yS C2H5 

)>CO + H.SC 2 H B = }CC + H 2 

cr; en/ x s— c 2 h 5 

H.SC2H5 

Acetone ethyl acetone-ethyl mercaptol 

mercaptan 
This can be oxidized by KMn0 4 to a sulphone: 

CR 3 y SC 2 H 5 CH 3x /S02C2H5 

/C^ + 20 2 = p>c/ 

CH3 SC 2 H5 CH3 S0 2 C 2 Ii5 

This is acetone diethyl sulphone or sulphone methane or 
diethyl sulphone dimethyl methane : The name is shown by the 
following steps: 
1. H H 



C (methane) 



H H 

2. CH. 

yC = O (acetone or dimethyl oxymethane) 

ch/ 

3. CH3. .SC2H5 

/C^ (acetone ethyl mercaptol or dimethyl 

CH 3 SC2H5 diethyl mercaptol methane) 

4. CH 3 ^OaCaHs 

/C^ (dimethyl methane diethyl sul- 

CH 3 SO2C2H5 phone or sulphonal). 

TRIONAL 
This differs from sulphonal in that one of the CH 3 groups is 
replaced by ethyl C 2 H 5 : 

('II;;, SO0C2PT5 

/C\ consequently it is diethyl sulphone 

(Ml/ \S0 2 C 2 H 5 
ethyl, methyl methane, It melts at 76°. 



THE SULPHONE GROUP 47 

TETRANOL 
This has all the replaceable hydrogen occupied by ethyl groups : 

2 5 \p/ 2 2 5 and is diethyl sulphone diethyl meth- 
C 2 H 5 / \o 2 C 2 H 5 ane " 

Since the pharmacological action of hydrocarbon radicals 
increases with the size of the molecule, we should expect trional 
to be more active than sulphonal. While this seems to be true 
for dogs, it does not seem to hold good for human beings. It 
should be emphasized that CH 3 , or the first of the series, is 
nearly alwaj^s an exception to the rule, both chemically and 
pharmacologically. 

Sulphones are not true esters, but bodies of remarkable sta- 
bility. They cannot be reduced to sulphides by nascent hydro- 
gen. However, their stability outside the body is no criterion 
of their pharmacological activity; since some of those that are 
most stable are physiologically reactive and more or less de- 
composed in the body, while some less stable outside the body 
pass through it unchanged and are inert pharmacologically. 

Ethylene diethyl sulphone : 

CH2.SO2C2H5 , V , SO2C2H5 ., 

and methylene p-rr / are easily 

Axr oa m tj di-ethyl sulphone 2 \ ^ o tt decomposed 
OXI2.0U2L/2.H.5 0U2O2AI5 

by alcoholic potash, but may be found unaltered in the urine, and 

are only slightly active physiologically, whereas, sulphonal, 

trional and tetronal, which are unacted on by alcoholic potash, 

acids, and many oxidizing and reducing agents, are decomposed 

in the body to some extent at least and are actively hypnotic. 

Chemical Tests 

Test solubility of each in water, alcohol, and ether. 

Heat 0.1 gm. of each separately with an equal amount of char- 
coal in a dry test tube. Each one will be reduced to the sulphur 
alcohol which is recognized by its odor, which is similar to 
garlic. 

Heat another portion of fusion in a test tube alone, S0 2 is 
given off and will bleach starch iodide, or methylene blue 
paper. 



48 CHEMICAL PHARMACOLOGY 

V. ALDEHYDES 

Aldehydes are the first oxidation products of primary alcohols. 
Primary alcohols contain the group R, CH 2 OH. Aldehydes 


contain the group RC<f^ . Where R may be H, CH 3 , C 2 H 5 , 

X H 
or any member of the marsh gas series. In the case of phenol 
groups with an aldehyde side chain, almost any complex may take 
the place of (R). 

Aldehydes may be prepared : 

1. By the oxidation of any primary alcohol; 



CH3CH2OH + = CH 3 — C/ + H 2 

X H 
/O 

2. C 6 H 5 CH 2 OH + = C 6 H 5 — C<( + H 2 

X H 
benzyl alcohol benzaldehyde 

3. By dry distillation of a calcium salt, with calcium formate: 
Ca(CH 3 COO) 2 + Ca(H.COO) 2 = 2CH 3 CHO + 2CaC0 3 or 

(C 6 H 6 COO)Ca + Ca(HCOO) 2 = C 6 H 5 COH + 2CaC0 3 

The mechanism of the reaction may be represented; 

CH 3 |COONa P 

lCOONa^ CH3C \ H + Na2C ° 3 
±1 

Any other method of oxidizing an alcohol or reducing an or- 
ganic acid may yield an aldehyde. 

General Properties of Aldehydes. Reactions. — The char- 

acteristic reactions are due to the group — -R — C<f which shows 

X H 
exceptional chemical reactivity: the H atom in combination 

O 
with — C<^ can be readily oxidized, by the action of oxidizing 
X H 






ALDEHYDES 49 

reagents. Since they are readily oxidized, aldehydes act as 
reducing agents; and when they are added to an ammoniacal 
solution in a test tube of silver nitrate the silver is precipitated 
as a silver mirror. For the same reason, they reduce Fehling's 
solution. 

They form addition products readily. This is due to the 
C = group which opens up in the form : C — and the free 

\ \ 
valences add anything in the form of H and X as follows : 



/) 




/OH 


CH 3 c/ 
X H 


+ HCN->CH 3 C^CN 
X H 



(a) For this reason, they are easily reduced by nascent hydro- 
gen the same primary alcohol from which they were derived 
being formed — 








/OH 
-»CH 8 C^-H 
X H 


CH 3 c/ 
X H 


+ H 2 



(6) When shaken with a saturated solution of sodium acid 
sulphite, a crystalline addition product is formed. 

H 

JO I 

CH 3 C/ + NaHS0 3 -+CH 3 — G-OH 

X H x S0 3 Na 

On heating this product with acid aldehyde is again liberated, 
(c) Aldehydes unite with ammonia to form aldehyde ammonia 

H 
CH 3 C( + NH 3 = CH 3 — C— O-H 



H 



NH 



Similarity with hydroxyl amine, NH 2 OH, hydrazines, etc., 
addition products are formed, the added product always breaking 
or ionizing into H and X. The H adds to the O of the 
aldehyde, and the X to the carbon. 



50 CHEMICAL PHARMACOLOGY 

Caustic alkalies differ from ammonia in their action on 
aldehydes. Instead of forming a definite compound they 
convert the lower aldehydes into resinous bodies of unknown 
composition. 

Formaldehyde H— C<? (Methanal) is the aldehyde of 
X H 
methyl alcohol CH 3 OH + O = CHOH + H 2 0. At ordinary 
temperatures it is a gas and liquefies at (minus) — 21°C. It 
may be prepared easily by heating a copper spiral and dropping 
it into methyl alcohol in a test tube. It may also be formed in 
the body from methyl alcohol. It can also be derived from hydro- 
gen and carbon monoxide under the influence of an electric cur- 
rent. At 600°C. it is dissociated into CO and H 2 . Minute 
amounts of it are found in plants where it is highly important, from 
a theoretical point of view, in the formation of carbohydrates. 
The steps involved may be represented by the following reactions: 
(Baeyer) 

1. C0 2 ^CO + O 

2. H 2 0->H + OH 

3. CO + H 2 ->CH 2 

4. 6(CH 2 0)->C 6 H 12 6 

or carbon dioxide and water may react: 

C0 2 + H 2 =CH 2 0+0 2 

In combination with ammonia it forms hexamethylenamine or 
urotropine. When it is evaporated on a water bath, it polymerizes 
to form paraformaldehyde (CH 2 0) 2 . Trioxy methylene (CH 2 0;3 
is a white crystalline compound that separates from formalde- 
hyde on standing. It liberates formaldehyde again when it is 
heated. 

Formaldehyde unites with amines, ammonia, sugars, dextrins, 
urea, tannic acid, proteins, and many other substances. It 
is -therefore, a strong antiseptic, a local irritant and a general 
protoplasm poison, yet it is surprising how much of it may be 
injected intravenously into an animal without killing it. The 
reason being that it is oxidized or polymerized rapidly in the body. 
Even though it does not kill, it may produce a severe nephritis. 
The irritation is probably produced by the union with an amine 
group of the proteins. 



ALDEHYDES 51 

The amine and aldehyde groupings may exist in the living pro- 
toplasm simultaneously. Loew explained the difference between 
living and dead protoplasm on a rearrangement of such a grouping. 
In the living or labile molecule or biogen he assumed the group- 
ing to be: 

H 

I 

— C— NH 2 

J y° 

— C — Of In the dead or stable form 
X H 

H 

I 
— C— N— H 

I I 
=C— C— OH 

I 

i 

H 

such a difference of course would be very difficult to prove. 

Formaldehyde is valuable in medicine chiefly as an antiseptic, 
disinfectant, preservative and cauterizing agent. A solution of 
37 per cent, by weight is known commercially as formalin. 

On account of its relative physiological inertness and great 
antiseptic powers, in vitro, it was thought that formaldehyde 
might be injected into the veins with benefit in cases of tuber- 
culosis and other infections. It is now known, however, that it 
is rather inert in the body because it is rapidly oxidized, and for 
this same reason it possesses relatively little antiseptic action 
in the body. In addition it shows no specificity. When the 
concentration in the body is sufficient to exert an antiseptic ac- 
tion, it will injure the tissues of the body just as readily as the 
bacteria within the tissues. Compounds of formaldehyde like 
hexamethylentetramine, that are decomposed in the body and 
excreted in the urine, are valuable in cases of infection of 
the genito-urinary tract and bladder. The concentration of 
the aldehyde in the urine is much greater than it is in the 
blood. 



52 CHEMICAL PHARMACOLOGY 

Tests for Formaldehyde 

In solutions which are not clear, or in food products which are 
to be tested for its presence it is necessary in many cases to distil 
and test the distillate from 100 to 200 grams of the substance 
which has been acidified with phosphoric acid. Phosphoric acid 
is used because it is a non-volatile acid and will not appear in the 
distillate. 

1. Add to the formalin solution, diluted if necessary, about 1 cc. 
of pure milk or a solution of peptone. Add 1-2 drops of 1 per 
cent, ferric-chloride solution. Carefully pour this solution into" 
a test tube containing about 10 cc. of strong H 2 S0 4 . See that 
the two solutions do not mix. At the point of contact a violet 
or blue ring will appear. If the solution containing the 
formaldehyde is too strong, the result will not be so clear. If 
the milk contains less than 1:10,000 formaldehyde, the color 
may not appear for some time. 

2. To the milk or peptone solution containing the formalin add 
double the volume of strong HC1 containing 1 cc. of 10 per cent. 
Fe 2 Cl 6 in each 500 cc. of acid. Heat to 80° to 90°C. in a white 
dish giving it a rotary motion to cause mixing. A violet color in- 
dicates formaldehyde. To test a suspected milk for formalin, 
use this same procedure. If the milk has stood for a long time, 
it may be necessary to distil it, as a firm combination of the 
formalin with the protein prevents the test to some extent. 

3. Lieberman's Test. — Mix some of the watery solution of 
formalin with a drop of 1 per cent, phenol and pour cautiously, 
on some concentrated H 2 S0 4 in a test tube. A crimson zone at 
point of contact indicates formaldehyde. 

The Cannizzaro Reaction. — In the body, if formalin be given 
intravenously, there is both oxidation and reduction of it with 
the formation of methyl alcohol and formic acid : 

JO 

2HC<f + H 2 = CH 3 OH + HCOOH 

The presence of HCOOH may be shown by collecting the urine, 
reducing it with hydrogen and testing for formalin. 

4. Rimini's Method. — To 15 cc. of the solution to be tested 
add 1 cc. of a dilute solution of phenyl hydrazine hydrochloride, 



FORMALIN TESTS 53 

then a few drops of 1 per cent, ferric chloride solution and finally 
concentrated HC1. A rose red color is given by formaldehyde. 
Milk can be tested without distillation bj^ this -method, but the 
test is more delicate if a distillate is used. Acetic aldehyde or 
benzaldehyde do not interfere with the test. 

5. Phloroglucinol Test (Jorissen). 

Take phloroglucinol 0.1 gram 
NaOH 2.0 gram 

Aq. q.s. 10.0 cc. Make solution 

To 10 cc. of milk or other fluid to be examined, add 2 cc. of this 
reagent by means of a pipette, placing the end of the pipette at 
the bottom of the tube in such a manner that the reagent will 
form a separate layer. A bright red color, not purple, is formed 
at the zone of contact, if formaldehyde be present. Some other 
aldehydes, give a yellow color. The red color forms quickly and 
soon fades. 

6. Phenylhydrazin HC1 Method. — Mix 5 cc. of the solution 
to be tested with 0.03 gram of phenylhydrazine hydrochloride and 
4 to 5 drops of a 1 per cent, solution of ferric chloride. Keep the 
test tube containing this in cold water and add slowly with con- 
stant shaking to prevent heating, 1 to 2 cc. of concentrated 
H2SO4. A precipitate is formed which can be redissolved by the 
addition of either alcohol or H2SO4; giving a red color. The 
alcohol extract of anything to be tested will also give the 
reaction. This test has been found to give reliable reactions in 
a dilution of 1 to 150,000 formaldehyde. Acetic aldehyde or 
benzaldehyde, does not interfere. 

7. Phenylhydrazine Hydrochloride and Ferrocyanic Method. 
This method can be applied directly to aqueous solutions or 
aqueous alcoholic extracts. To from 3 to 5 cc. add the size of a 
pea of phenylhydrazin hydrochloride and 2 to 4 drops (not more) 
of a 5 per cent, to 10 per cent, solution of potassium ferrocyanide 
and from 8 to 12 drops of 12 per cent. NaOH. A distinct green 
or bluish green reaction is obtained in a dilution of 1-80,000 
formaldehyde. 

Acetic and benzaldehyde give a color from red to brown and 
mask the formaldehyde reaction. It is characteristic only when 



54 



CHEMICAL PHARMACOLOGY 



a clear green color is obtained. The method is "not applicable 
where blood coloring matter is present, but can be used with milk 
directly. 

HEXAMETHYLENAMINE 

Formaldehyde reacts with ammonia to form hexamethylen- 
amine. The reaction is GCH 2 + 4NH 3 = (CH 2 ) 6 N 4 + 6H 2 0. 
This is represented as — 



'N- 



1. CH 



/ 



\ 



H. : 



CH 2 

I 

N 

/ \ 
CH 2 CH, 



N 



\ 



N 



or 



/CH 2 
N— CH 2 



,CHj 



X' 



:ch 2 



N 



\ 



CH ; 



X CH 2 / 

It is a feebly basic crystalline solid, which dissolves readily in 
water. 

Hexamethylenamine is a valuable remedy in some cases of 
cystitis and infections of the urinary tract. It has also been 
used in laryngitis, pharyngitis, poliomyelitis, etc. It has but a 
slight irritating action, and only when taken in excessive amounts, 
does it cause nephritis or other untoward symptom. It is 
found on the market under a variety of names such as urotropin, 
cystogen, cystamine, hexamine, etc. 

It has some solvent action on uric acid, and has been recom- 
mended in gout; but the concentrations that dissolve uric acid 
never obtain in th<* organism. It forms a number of additive 
products which have been introduced into medicine, such as 
amphotropin which is a combination with camphor; cystopurin, 
with sodium acetate; formurol with sodium citrate; cystazol, 




FORMALIN TESTS 55 

with sodium benzoate. New urotropin, or helmitol, is anhydro- 
methylene citric acid: 

CH 2 CO 

I 

:— CH 2 — COOH 

CHo- COOH 
None of these compounds have any advantage over hexamethylen- 
amine. 

1. Mix 0.1 gram each of hexamethylenamine and salicylic 
acid. Add 5 cc. H 2 S0 4 and heat moderately. A carmine-red 
color is produced. 

2. An aqueous solution heated with dilute H 2 S0 4 liberates 
formaldehyde. If the acid solution is made alkaline with NaOH 
and heated gently, NH 3 is given off. 

3. Test the reaction of urine. Take 5 grains of hexamethyl- 
enamine. In 30-60 minutes collect the urine. Note the reaction. 
Acidify and distil 10-20 cc. Test the distillate for formaldehyde. 
It may not be necessary to distil the urine before testing. Make 
the test before distillation and, if in doubt, distil and test. 

ACETALDEHYDE, ALDEHYDE OR ETHANAL 

CH 3 — C<^ is not used in medicine, but some of its derivatives 

paraldehyde, chloral and chloral hydrate are important. From a 
purely chemical point of view, acetaldehyde is perhaps the most 
important aldehyde. It is a colorless liquid, B. P. 21°, sp. gr. 0.8, 
soluble in water, alcohol, and ether, dissolves phosphorus, sulphur, 
iodine. It occurs as a by-product in all sugar fermentations. 
The following method of preparation illustrates strikingly some 
of the characteristic reactions of aldehydes : (after Remsen) : 

Place 120 grams of granulated potassium bichromate in a 1 to 
2 liter flask A. 

(a) Place a stopper with two holes in the flask, and set on 
water bath. 

(6) Insert a funnel tube in one opening and a condenser in 
the other. Elevate the condenser at an angle of 45°, so that it 



56 



CHEMICAL PHARMACOLOGY 



acts as a reflux. Connect the free end of the condenser by means 
of rubber and a glass tube (E) with cylinders F and G, half -filled 
with ether. The glass tubes E and / should dip well into the ether. 

Make a mixture of 100 cc. concentrated H2SO4 water 400 cc. 
and alcohol 120 cc. Cool the mixture to room temperature and 
pour it slowly into the flask. 

If the liquid is added too rapidly to the bichromate mixture, 
the action may be too violent. Some alcohol may enter the 
condenser and flow back again into the flask. The aldehyde is 
soluble in the ether. Supply the condenser with water at about 




Fig. 1. 

30°C. Heat is applied to finish the distillation. After the 
reaction is ended, the connections are broken and dry NH 3 gas 
is passed through the cold ethereal solution of the aldehyde. 

Crystals of aldehyde ammonia are deposited. The ether and 
the crystals are poured on a filter and the crystals washed with 
ether. The pure crystals are then placed in a flask and sulphuric 
acid added when aldehyde is liberated. It may be distilled 
and condensed in a vessel surrounded by ice. 

The reactions involved in the preparation of acetaldehyde are : 
CH 3 CH 2 OH + O-+CH3CHO + H 2 



PARALDEHYDE 57 

If one inhales fumes of acetaldehyde there is a feeling of suffoca- 
tion with coughing. In animals its irritative action causes excite- 
ment followed by depression, and paralysis of respiration. A 
considerable portion of ingested aldehyde is oxidized in the body, 
traces escape in the breath and more in the urine. Kunkel 
describes a condition of aldehydeismus in people exposed to alde- 
hyde fumes. In such cases there is thickening of the adventitia 
of the vessels and an increase of connective tissue between the 
lobes of the liver. 

PARALDEHYDE 

(CH 3 CHO) 3 . This is the polymer of acetaldehyde. It is 
detected only after being reconverted into acetaldehyde. 
Graphic formula: 

O , 



/ /\ 

CH 3 — CH CI 

1 / 


I— CH 3 


i \ 

\ c 

\>( 

CH 

CH 3 

Par acetaldehyde, or 


) 

paraldehyde 



Paraldehyde is little used in therapeutics because of the per- 
sistent disagreeable taste. Formerly it was commonly used in 
medicine as a hypnotic. It is used now chiefly in delirium 
tremens — where it is often more efficacious than other sedatives. 
The dose is 0.5 gram but the patient soon becomes accustomed to 
it and if larger doses are given to get the effect, tremors, delirium, 
hallucinations and epileptiform convulsions may result. 

CHLORAL AND CHLORALDEHYDE 

Chlorine is an oxidizing agent. When it acts on alcohol, 
chlor aldehyde is formed as follows : 

1. CH 3 CH 2 OH + Cl 2 ->CH 3 CHO + 2HC1 

2. CH 3 COH + 6C1->CC1 3 CH0 + 3HC1 



58 CHEMICAL PHARMACOLOGY 

There are many intermediate reactions in this, but the above 
are the essential steps. An important intermediate reaction is 
the union of alcohol and the aldehyde to form acetal; 

CH3 OH.C2H5 CH3 

I I y OC 2 H 5 

C = O + ->C/ + H 2 

i I X OC 2 H 5 

H OH.C ? H 5 H 

Acetal 

Acetal is an uncertain hypnotic and produces unpleasant heart 
depression, and patients soon become habituated to it. By 
analogy one would think that water HOH would react with 
acetaldehyde to form an addition product, e.g. : 

CH3 CH3 

I OHH I ,OH 
C=0 + = C<" + H 2 

I OHH I X OH 
H H 

But there is a general law in organic chemistry that a single carbon 
atom cannot hold two OH groups. As a result, another molecule 
of water is eliminated and the aldehyde reformed. With 
chloraldehyde (chloral), however, the CI in the molecule so 
modifies the action of the carbon atom that it does hold two OH 
groups in firm union. Chloral for this reason is the exception. to 
the rule. 

CHLORAL AND CHLORAL HYDRATE (Chloraldehyde) 

Chloral is a colorless oily liquid with a pungent odor and acrid 
taste, while chloral hydrate is crystalline. Chloral itself is 
little used, the hydrate being very commonly used. 

Chloral, CCl 3 CHO + H 2 = CC1 3 CH(0H) 2 , chloral hydrate. 

Chloral hydrate like aldehydes is irritant to the skin and mu- 
cous membranes and is a very disagreeable drug to take. For 
these reasons if given in too concentrated a form it may cause 
vomiting. The burning or irritant action may be followed by 
some local anesthesia. When administered it should be well 
diluted with water and a flavoring agent like syrup of orange or 
citric acid. After too large a dose there may be hemorrhages in 



CHLOEALDEHYDE , 59 

the stomach and intestines, and sometimes in nose and lungs. 
By its continued use catarrh of the stomach and a skin rash fre- 
quently develop. With toxic doses the blood pressure and body 
temperature sinks, respiration is weakened, cyanosis, coma, and 
edema of the lungs result. All the symptoms of alcoholic in- 
toxication may precede these symptoms. 

The Fate of Chloral in the Body 

Because chloral or chloral hydrate yield chloroform when heated 
with KOH, Liebrich explained their hypnotic action, by assum- 
ing that they yielded chloroform in the body. Chloral, however, 
is not decomposed to any extent in the body. The fate of chloral 
in the body is interesting since it is reduced rather than oxidized. 
It is well known that both oxidations and reductions occur in 
the body, but oxidations are much more frequent, and apparently 
more important. The fate of chloral seems to be as follows: 

1. Chloral is reduced to the corresponding alcohol, trichlor- 
ethylalcohol. 

CCI3CHO -> CC1 3 CH 2 0H 

2. The alcohol combines with glycuronic acid and the combi- 
nation is urochloralic acid, or C 8 HiiCl 3 07. This substance 
reduces Fehling's solution, but does not ferment with yeast. It 
is also decomposed into the alcohol and gfycuronic acid on boil- 
ing with dilute acids. The combination of trichlorethyl alcohol 
and glycuronic acid may be represented as follows : 

COOH COOH COOH 



CH.OH CH.OH 

1 1 




CHOH 


1 1 
CH.OH CH.OH 




CH X 

1 \ 
->H 2 + CHOH \ 

CHOH/ 

chA).ch 2 .cci 3 

Urochloralic acid 


1 "I 
CH.OH + CCl 3 ->CH.OH 




CHOH CH 2 CH.OH 

1 | | OH 
CHO OH CH^ 

X O.CH 2 
Glycuronic acid 


.CCI3 



60 CHEMICAL PHARMACOLOGY 

It should be noted in this representation that the glycuronic 
acid is formed before the union with the alcohol. As a matter 
of fact, such union of the alcohol with glucose may be necessary 
for the formation of glycuronic acid in the body (see p. 175, 
glycuronic acid) . 

1. Heated with KOH, chloral or its hydrate yields chloroform. 
Dissolve 0.5 grams chloral hydrate in 5 cc. of water, add a few 
drops of KOH and heat. Note the odor. CCl 3 CHO + KOH 
— > CHCI3 + HCOOK. All alkaline hydrates, carbonates, and 
borax cause this decomposition. 

2. Like all aldehydes, chloral reduces Fehling's solution, and 
alkaline silver nitrate solutions. 

3. In alcoholic solutions, with NaBr, or KBr, chloral forms 
chloral alcoholate 

OC 2 H 5 
CC1 3 CH^ an oily liquid 

X)H 

4. Chloral triturated with camphor, acetanilide, acetphenetidin, 
urethane, phenol, salol, or thymol, produces a liquid. Use equal 
parts of chloral and the others, to show this. Such combinations 
are incompatible in prescriptions (pharmaceutic or physical 
incompatibility) . 

5. It is also incompatible with antipyrine with which it forms 
C13H15H2O3CI3 (hypnal) and C13H13CI3H2O2 (chloral antipyrine). 
Hypnal resembles chloral hydrate in action while chloral anti- 
pyrine is inert. 

6. A solution of chloral hydrate with a little resorcinol and a 
few drops of NaOH gives an intense red (rosolic acid), which is 
destroyed by HC1. 

7. With ammonium sulphide, chloralhydrate gives an orange 
color, changing to brown. The color develops more quickly on 
warming. 

8. Chloral is sometimes given as a poison ("knock-out drops"). 
In such cases, it is excreted in the urine. To obtain chloral from 
the urine, acidify with tartaric acid and distil. To obtain the 
whole of the chloral from the urine, it is necessary to distil in 
vacuum almost to dryness. Test the distillate for chloral. 



CHLORALOSE 61 

To Test Urine Directly for Chloral 

Caution: This is dangerous. To about Jl$ of a test tube 
full of urine add one drop of anilin, then add 2 cc. of an alcoholic 
solution of NaOH. If chloral is present, it will be manifested 
by the disagreeable odor of phenyl isocyanide or carbylamine 
C 6 H 5 NC. 

Chloroform also gives this reaction: 

CHCI3 + C 6 H 5 .NH 2 = C 6 H 5 .NC + 3HC1 

This is a very poisonous substance and must be handled with care. 
The products should be washed away through a sink pipe in a 
draught closet. 

9. Pure chloral hydrate does not give the iodoform reaction. 

10. Nessler's Solution Test. — Add a few drops of Nessler's 
solution to aqueous chloral hydrate and shake. A yellowish 
red precipitate forms changing to yellowish green. This is an 
aldehyde reaction. 

11. Boil an aqueous solution of chloral hydrate with 0.3 gram 
solid sodium thiosulphate. A turbid brick red liquid results. 
KOH changes this to brownish red. 

Chloralose is compound of chloral and grape sugar. It is 
made by heating together anhydrous chloral and glucose: 

CCI3CHO + C 6 H 12 6 = CgHnClsOe + H 2 

The introduction of the sugar into the molecule makes it act more 
like morphine than chloral, and it may produce restlessness, 
tremors and hemoglobinuria. Large doses by heightening the 
reflexes may produce strychnine-like convulsions. Why such a 
combination should so change the action of the original drug is 
beyond chemical explanation. All these compounds illustrate 
the reactivity of aldehydes. 

Chemical Tests 

1. Soluble — freely in hot water. Less readily in cold. 

2. When hydrolyzed it yields glucose and chloral. 

The compounds of bromine and iodine corresponding to chlo- 
ral have no uses in medicine. 



62 CHEMICAL PHARMACOLOGY 

VI. KETONES 

When primary alcohols are oxidized they yield aldehydes, 
while secondary alcohols yield ketones. Propyl alcohol (pri- 
mary) CH 3 CH 2 (CH 2 OH) on oxidation yields CH 3 CH 2 CHO, 
propyl aldehyde. Isopropyl alcohol (secondary) CH 3 CH(OH)- 
CH 3 , yields CH 3 CO.CH 3 , acetone. Ketones have the general 

R \ 

formula /CO 

W 
Ketones are also prepared by the distillation of the calcium salt of 
the corresponding acid. The reaction has been most carefully 
studied in the distillation of calcium acetate, and the ketone from 
this is called acetone. The reaction takes place according to the 
following equation: 

CHg—COO x CH 3x 

pCa -> pCO + CaC0 3 

CH 3 — COCK CH/ 

ACETONE 

Acetone, CH 3 CO.CH 3 is the most important ketone. It is 
of importance principally as a solvent, and in the preparation 
of chloroform, sulpho-methanum (sulphonal), etc. It has been 
used as an anesthetic, hypnotic and anthelmintic, but its use is 
now restricted to its solvent action, and the preparation of other 
drugs, especially the sulphone group of hypnotics. 

It is a pathological constituent of urine, especially in diabetes 
and severe forms of cancer (carcinomatous acetonuria). It 
has also been found in the urine after poisoning with the following 
drugs (toxic acetonuria) phosphorus, carbon monoxide, atropine, 
curara, antipyrina, pyridine, male fern, chronic lead poisoning 
and in morphinism after discontinuance of the drug. 

Secondary alcohols are more toxic than primary. Isoprop3 r l 
alcohol in the case of rabbits is about five times as toxic as propyl. 
Two grains of isopropyl alcohol in a rabbit produces drowsiness 
and sleep. Acetone, however has feeble narcotic properties and 
is less toxic than ethyl alcohol. Archangelsky found that dogs 
show signs of narcosis when the blood contains 0.5 per cent, 
acetone. Smaller doses produce narcosis in rabbits, but the 
toxic action is not great. Urine almost always contains some 
acetone which is increased in diabetes and protracted fevers, 



ACETONE 63 

such as typhoid, tuberculosis and pneumonia. It has also been 
observed in the urine in various nervous and mental diseases. 

Chemical Tests 

1. Test solubility of acetone in water, alcohol, ether, chloro- 
form and volatile oils. Note the odor. 

2. Acetone is formed by the distillation of calcium acetate. 

Ca(CH 3 C0 2 ) 2 = CH3COCH3 + CaC0 3 

3. Acetone occurs in the urine in diabetes. It yields iodoform 
when treated with iodine solution as does alcohol. See tests 
under alcohol. 

4. Legal's Test. — To 1 drop of acetone in 5 cc. of water, add 
an equal volume of freshly prepared sodium nitro-prusside and a 
few drops of NaOH. A red color results which becomes darker 
on adding acetic acid. Creatinine gives this same red color 
but it disappears on adding acetic acid. 

5. Acetone differs from aldehyde as follows: 
(a) It does not polymerize. 

(6) It does not reduce ammoniacal solutions of silver Irydroxide. 
(c) It is oxidized only by moderately powerful reagents and 
when oxidized yields acetic acid, carbon dioxide and water. 

6. Acetone gives Lieben's iodoform test (page 23), even when 
NH4OH is used instead of NaOH or KOH. 

7. Penzoldfs Test. — Add acetone and a few drops of NaOH 
(5 per cent.) to a saturated aqueous solution of ortho-nitro- 
benzaldehyde. The mixture becomes yellow, then green on 
standing and after 15 minutes a blue precipitate of indigotin is 
formed. When shaken with chloroform indigotin goes into 
solution and colors the chloroform blue. 

8. Reynold's Test. — Freshly precipitated mercuric oxide is 
dissolved by acetone. Add a little mercuric chloride, and an 
equal volume of alcoholic KOH to an acetone solution. Shake 
thoroughly and filter. To the filtrate add (NH^S to form a 
layer. A black ring of HgS indicates that some mercuric oxide 
was dissolved. 

CHLORETONE 

Chloretone is acetone chloroform 

CR S CR 3 OH 

^>GO + CHCI3 = ^C^ 
CH3 OH3 CCL 



64 CHEMICAL PHAKMACOLOGY 

It is produced by the action of caustic alkalies on a mixture 
of acetone and chloroform. It is a peculiar camphoraceous 
crystalline body, sp. gr. 0.792 at 20°C. It is miscible with water, 
alcohol, ether, volatile and fixed oils. Calcium chloride sets it 
free from its aqueous solution. It reduces Fehling's solution. 

It is more dangerous than chloral and is therefore little used 
except for laboratory animals. The mechanism of the action is 
unknown. Anesthetics or hypnotics when taken by mouth 
have the disadvantage that they cannot be removed if too much 
has been taken. In case of ether and chloroform, if it isseen 
that too much is being given, the drug can be removed and the 
excess in the body is soon exhaled. 

Chloretone is less irritant to the stomach and it has been used 
to some extent as a substitute for chloral. It has also some local 
anesthetic properties, and has been used in the dressing of wounds, 
either in the form of dusting powder or in solution. 

The fate of chloretone in the body is unknown. After the 
administration of large doses Houghton and Aldrich could not 
find it in any of the secretions or excretions and concluded that 
it is destroyed in the body. 

VII. ORGANIC ACIDS 

Organic acids are either the second products of the oxidation 
of alcohols, or the third products of the oxidation of hydrocarbons : 



I 


II 


III 


IV 


C2H6 


C 2 H 5 OH 


CH3CHO 


CH3COOH 


ethane 


alcohol 


aldehyde 


acid 



The characteristic acid group is carboxyl — COOH. The basi- 
city of the acid depends upon the number of the carboxyl groups 
in the acid. 

When salts are formed, substitution of the carboxyl hydrogen 
takes place: 

CH3COOH + NaOH = CH 3 COONa + H 2 

The introduction of the COOH group into the hydrocarbon or 
alcohol changes the toxicity of the members and of the methane 
series but slightly. With the dibasic acid the proximity of the 



FORMIC ACID 65 

COOH groups in the molecule seems to have some influence. 

POOH 

Thus in oxalic • ^^^ where the carboxyls are closer than in 
COOH 

y COOH 
malonic CH 2 <^ the toxicity is greater. 

In the aromatic series, the introduction of a carboxyl lessens 
the toxicity. Benzoic acid C6H5COOH is less toxic than benzol. 

,COOH 
Amino benzoic acid, C 6 H 4 ^ is less toxic than aniline, 

X NH 2 

OH 
C 6 H 5 NH 2 . Also, salicylic acid, C 6 H 4 <^ is less toxic than 

X COOH 
phenol. 

Acids of the paraffin series or their salts that are absorbed, 
are oxidized to carbonates in the body and increase the alkalinity 
of the blood. Aromatic acids are excreted chiefly in combination 
with glycuronic, amino acetic, or sulphuric acids. 

ORGANIC ACIDS OF METHANE SERIES 

Methyl alcohol, when oxidized, gives formaldehyde, and if 
oxidation proceeds far enough, formic acid : 

/° 
CH3OH + 0->HC<( + H 2 

X H 

Formaldehyde 

HCr + 0->HCOOH 

H Formic acid 

Formic acid as such is not important in medicine. It occurs 

in nettles and in the sting of insects and is formed in the body 

when formaldehyde or any of its preparations are taken. The 

rate of formation of acid from aldehyde is so slow in comparison 

with the rate of oxidation that it is oxidized to C0 2 and H 2 

about as rapidly as it is formed. Only under special conditions 

may it be found in the blood or urine. Dakin finds that formic 

acid is a constant constituent of the urine during fasting and the 
5 



66 CHEMICAL PHARMACOLOGY 

quantity is considerably increased after carbohydrate and fat 
ingestion and to a lesser extent also after protein ingestion. All 
three classes of food substances yield formic acid as an end prod- 
uct of metabolism but it is so readily oxidized that it is eliminated 
in only small amounts in the urine. 

It is the strongest acid of the series and much more toxic than 
other members except butyric which also has some narcotic 
properties. In presence of metallic rhodium it is spontaneously 
decomposed into hydrogen and carbon dioxide. This mechanism 
may be of value in the explanation of fermentation by assuming 
that yeast produces an organic catalyst that acts similarly. 

It has been employed internally in rheumatism, and locally by 
allowing bees to sting the involved part. The local hyperemia 
so caused is beneficial. 

In the presence of alkali, or when introduced into the body, 
formic aldehyde shows the phenomenon known as the Canniz- 
zaro reaction, i.e. there is both an oxidation and reduction of the 
aldehyde; 

2HCHO + H 2 0->CH 3 OH + HCOOH 

ACETIC ACID 

Acetic acid is formed from ethyl alcohol in the same manner 
that formic acid is prepared from methyl alcohol. 

J° 

C 2 H 5 OH + =CH 3 C^f + H 2 

X H 

JO 
CHaCkf 4- O = CH 3 COOH 

It has a wide use in medicine and as a food. Vinegar is impure 
acetic acid. In therapeutics the acetates are used as diuretics 
and refrigerants. Acetic acid is used as a solvent and preserva- 
tive in pharmacy; aceta are solutions of drugs in acetic acid. 

Acetic acid is oxidized in the body to C0 2 and H 2 0. The 
C0 2 combines with the bases of the body and renders the urine 
alkaline. Nearly all organic acids of methane series are oxidized 
in this way and are excreted as carbonates. They lessen the H 



ACETIC AND CARBONIC ACIDS 07 

ion concentration of the blood and act as diuretics, both because 
of their alkalinity and their salt action. 

However the capacity of the animal body to oxidize acetic 
acid is limited and normal human urine contains on the average 
between 50 and 300 mgm. per day. 

Amino-acetic acid or glycocoll CH 2 NH 2 COOH occurs in the 
body as a constituent of proteins and the bile acids, and in the 
urine of horses as hippuric acid. When benzoates are taken as 
medicines, they are excreted combined with glycocoll as hippuric 
acid; 

C 6 H 5 COOH+H 2 NCH 2 COOH = C 6 H 5 CO.NH.CH 2 COOH + H 2 

In the same way salicylic acid combines with glycocoll to 
form salicyluric acid 

,OH 

X CO.NH.CH 2 .COOH 

Recent work by Hanzlik throws some doubt on the occurrence 
of this reaction in the body. Note that salicyluric acid is in no 
way related to uric acid as the name might suggest. 

CARBONIC ACIDS 

This acid is described both in organic and inorganic chemistry; 

CO(^ nT r. It is not known in the free state, but its salts are 

extremely important in medicine. It is thought to exist in 
solutions of carbon dioxide and water, and in the blood. 
It forms amides and salts like a dibasic acid. 



JOH 

X OH 


/NH 2 
X OH 


y NH 2 ,NH 2 
X OC 2 H 5 X NH 2 


Carbonic 


carbamic 


urethane urea 


acid 


acid 




X NH 2 
X ONH 4 


X>Na 
CO( 

X ONa 


ammonium carbamate 


sodium carbonate, etc. 



68 CHEMICAL PHARMACOLOGY 

The salts of carbonic acid are much used in therapeutics in 
effervescent cathartics, as antacids, in baking powders, many 
beverages, such as soda water, potash water, champagne, and 
other sparkling wines. Effervescent cathartics are essentially a 
carbonate or bicarbonate mixed with an organic acid of such a 
nature that the salt formed is but little absorbed from the gastro- 
intestinal tract, such as the citrates, tartrates, malates, etc. 
The CO2 liberated masks the taste of many medicines and has a 
stimulating action on the gastro-intestinal tract. Absorption is 
hastened by it. It is excreted, much of it by eructation, some 
is absorbed and given off by the lungs. It is tjie normal stimulus 
of the respiratory center, but has slight action on the organism 
after absorption. This substance is slightly irritating to mucous 
membranes and by its action on the stomach may increase appe- 
tite. On prolonged application it has an anesthetic action. 
Because of this action carbonic acid or effervescent drinks are 
used to allay vomiting. Carbon dioxide snow is used especially 
for local anesthesia, this being due more to freezing than to 
specific action. The hydrogen ion concentration of the blood 
can not be altered appreciably by the acid or carbonated drinks, 
but can be changed by the soluble carbonates. 

The amount of carbon dioxide in the air should not exceed 
.03 per cent, but 3 per cent, will produce no immediate toxic 
symptoms. It is only when CO2 reaches 5 per cent, that it 
produces poisonous symptoms. It is not nearly so toxic as 
methylene and many other gases. The toxic effects produced 
in crowded rooms, formerly thought to be due to CO2, are mainly 
due to the heat and moisture, always present in such cases. 

UREA 
,NH 2 
Urea = CO^ is the diamide of carbonic acid: 

X NH 2 

X>H 
CO( 
\)H 

It is of interest as the basis of veronal, which is diethylmalonyl 
urea. A compound of the hydrochloride of quinine and urea, 
C20H24O2N2HCI. CO(NH 2 ) 2 HC1, is used as a local anesthetic. 



OXALIC ACID 69 

The urine on an average diet contains about 2 per cent, urea, 
which acts as a diuretic. According to Fosse, also Bamberger 
and Landsiedl, it occurs in very small amounts in higher plants 
and has also been reported in bacteria. Plants can use urea as a 
source of nitrogen, and microorganisms can convert it into am- 
monium carbonate. 

/NH 2 
CO( + 2H 2 0<=±(NH 4 ) 2 C0 3 

X NH 2 

Besides being the main end product of protein digestion urea is 
of interest in relation to Wohler's synthesis of ammonium cyanate 
into urea, which was the first organic substance artificially 
prepared : 

y NH 2 
NH 4 CNO->CO^ 

X NH 2 

OXALIC ACID 
COOH 

Oxalic acid, | is of importance in medicine only as a 

COOH 
toxic agent. It is toxic because it removes calcium, which is 
necessary for life, and is, therefore, a general protoplasm poison. 
Also, because it precipitates calcium, it prevents the clotting of 
blood, and prevents rennet from clotting milk. 

Its relation to cellulose and the sugars is seen from the fact 
that sugars, starches, and cellulose yield oxalic acid when boiled 
with nitric -acid. Its presence in the urine in some instances 
may arise from incomplete oxidation of carbohydrates. Its 
relation to CN is seen from the following formula: 
CN COOH 

| + 4H 2 = | + 2NH 3 

CN COOH 

2NH 3 + (COOH) 2 = (COONH 4 ) 2 ammonium oxalate 
Oxalic acid is related to formic acid. When sodium formate 
is heated rapidly, sodium oxalate is produced : 

NaCOoiil NaOOC 

■ i = I + h 2 

NaCOOlHi NaOOC 



70 CHEMICAL PHARMACOLOGY 

Under proper conditions especially when heated in glycerine, 
this reaction may be reversed, and oxalic acid carefully heated 
will yield formic acid. 

COOH 

| -> HCOOH + C0 2 

COOH 

Soluble calcium salts precipitate oxalates as calcium salts. 
These salts are, therefore, antidotal to oxalates. Whether or not 
any oxalic acid can be oxidized in the body, is a disputed ques- 
tion. Marfori claims that 30 per cent, of the amount taken 
reappears in the urine while Faust found 100 per cent. Hilde- 
brandt, found that 60 per cent, of oxalic acid injected subcu- 
taneously in rabbits was oxidized. Dakin found 90 per cent, 
oxidized under the same conditions. It appears in the urine as 
" envelope" crystals. These may be sufficient to block the tu- 
bules and cause nephritis. Glycosuria and indicanuria occur 
frequently, after large doses of oxalates. Tomatoes, spinach, 
rhubarb, sorrel, and other plants contain considerable oxalate, 
and most of this when eaten appears in the urine. In some 
cases oxalate poisoning has been caused by these plants. 

MALON1C ACID 

COOH 
Malonic acid, CH 2 <^ is the next higher homologue of 

X COOH 
oxalic acid. The use of the cyanides in building up compounds is 
illustrated in the formation of malonic acid, which is formed from 
monochloracetic acid: 

CN COOH 
CH 2 C1 | 

| + KCN + H 2 -> CH 2 -> CH 2 + KC1 

COOH | | 

COOH COOH 

Malonic acid is a crystalline compound, which melts at 132°C. 
It is found in nature in the juice of beets, where it occurs as the 
calcium salt. It is a constituent of veronal. Barbituric acid 



DICARBOXYLIC ACIDS 71 

or malonyl urea is obtained from alloxantin by heating it with 
concentrated sulphuric acid and from dibrombarbituric acid 
by the action of sodium amalgam. Veronal (q.v.) is diethyl 
malonyl urea or diethyl barbituric acid. 

SUCCINIC ACID 

Oxalic, malonic and succinic acid form an homologous series 
of dibasic acids: 

COOH XJOOH CH 2 COOH 

CH 2 v 

COOH X COOH CH 2 COOH 

oxalic malonic succinic 

None of these are used to any extent in medicine. As the 
COOH groups become more widely separated in the molecule 
the toxicity decreases; hence malonic acid is less toxic than oxalic. 
This is still further exemplified in citric and tartaric acids. 

Succinic acid occurs in amber, fossil wood, in many plants, 
asparagus, etc., in brain, muscle and in the urine after the in- 
gestion of plants containing it. It may be prepared from it's 
elements by forming acetylene from carbon and hydrogen. This 
is reduced to ethylene. If ethylene be passed into bromine, 
ethylene dibromide is formed : 

CH 2 CH 2 Br 

I + Br 2 = I 
CH 2 CH 2 Br 

This when treated with an alcoholic solution of KCN forms 
CH 2 CN 
CH 2 CN 
which is hydrolyzed to -h> CH 2 COOH.CH 2 COOH. 
. TARTARIC ACID 

Tartaric acid may occur in levo, dextro, meso, and racemic 
forms . It is dihydroxy succinic acid : 

CH 2 COOH OHOH.COOH 



1 



CH 2 COOH CHOH.COOH 

succinic tartaric 

acid acid 

t was on these acids that Pasteur made his important dis- 



72 



CHEMICAL PHARMACOLOGY 



coveries on the polarization of light by organic substance. He 
found that certain crystals dissolved in water turned the polarized 
ray to the left. Others turned it to the right; and a mixture of 
the two was racemic or inactive (external compensation). On 
studying the composition of the organic substances, he found that 
the active crystals are mirror images of each other. It has been 
found that only those with an asymmetric carbon are optically 
active. No single base of an organic substance is known that is 
optically active without the presence of an asymmetric carbon 
atom. However a substance may contain two asymmetric 
C-atoms and be inactive. This occurs in the meso form of 
tartaric acid, cf. formula III. This is internal compensation. 
The importance of this physico-chemical property to living mat- 
ter can hardly be estimated. The mould, penicillium glaucum, 
ferments dextro, but not levo tartaric acid. Yeast will ferment 1. 
fructose, 1. glucose, 1. mannose, or 1. galactose. Dextro epine- 
phrine is only about 3^2 as toxic as 1. epinephrine; d. hyoscyamine 
is but feebly active in comparison with 1. hyoscyamine. It is 
probable that time will greatly emphasize the relationship of 
optical properties and life processes. 

The levorotatory form is represented in formula (I), the dextro 
in (II), and meso tartaric in (III). 

(I) (II) (III) 

COOH COOH COOH 



HO— C— H H— C— OH 

I ' I 

H— C— OH HO— C— H 



HO- 



-H 



HO— C— H 

I 



COOH COOH COOH 

The central C atoms in (I) and (II) are asymmetric (each 
valence has a different element or radical in combination), so 
that when both forms are in the same solution, the influence of 
one on polarized light neutralizes the other. 

Tartaric acid is used in medicine as an expectorant and emetic 
in tartar emetic, which is antimonyl potassium tartrate. 

,CHOH COOHK . 



1 



'\ 



:H 2 



CHOH COO(SbO) 



CITRIC ACID 73 

2. Rochelle Salt, or sodium potassium tartrate, C 4 H 4 6 K Na 
+ 4H 2 0, is used as a cathartic and antacid. 

3. The acid salt of tartaric acid is used in domestic economy 
as cream of tartar or baking powder. The essentials of a baking 
powder are: something that will liberate C0 2 slowly and effi- 
ciently, and will not leave a harmful or toxic residue in the food. 
Cream of tartar fulfills these conditions. The reaction in this 
case is: 

CHOH.COOK CHOH— COOK 

| + NaHC0 3 = + H 2 + C0 2 

CHOH.COOH CHOH— COONa 

Cream of tartar sodium potassium tartrate 

CITRIC ACID 

CH 2 — COOH 
I /OH 

Citric Acid, C^ occurs in. the juice of many 

| X COOH 
CH— COOH 

plants, especially in lemon juice, where it may reach 5 per cent, 
and in gooseberries, 1 per cent. It is also found in raspberries, 
currants, and other acid fruits, and is said to be found in the 
milk of animals, probably being derived from the food. It is 
formed in the fermentation of glucose by citromycetes pfefferi- 
anus. In medicine its use is as a substitute for lemon juice; in 
the syrup of citric acid as a vehicle and refrigerant. Magne- 
sium citrate is a much used cathartic in iron and ammonium 
citrate as a soluble form of iron in citrated caffeine, etc. 

Citrophen or citrophenin is a combination of citric acid and 
phenacetin : 

CH 2 .CONHC 6 H 4 OC2H 5 

COH.CONHC 6 H 4 OC 2 H 5 

I 

CH 2 CONHC 6 H 4 OC 2 H 5 . It is used as an analgesic and 
antipyretic. 

The reactions of acetic acid, acetone, and citric acid are inter- 



74 CHEMICAL PHARMACOLOGY 

esting, and the relationship also shows how the cyanides may be 
disintoxicated by the body. Calcium acetate when distilled gives 
acetone: 

CH 3 .CO(X CH-k 

pCa = ">CO + CaC0 3 

CH 3 .COO X CH/ 

If chlorine is conducted through cold acetone, dichlorace- 
tone is formed : 

CH 2 C1 CH 2 CN 

I I 

C = +2KCN-^C = + 2KC1 

I 'I 

CH 2 C1 CH 2 CN 

Dichloracetone Acetonedicyanide 

When this is hydrolyzed it. gives acetone dicarboxylic acid; and 
this gives citric acid as follows: 

CH 2 COOH CH 2 COOH CH 2 COOH 

I I y 0H I / 0H 

CO + HCN = C<^ + 2H 2 Q -> C^ 

| | X CN | X COOH + NH 3 

CH 2 COOH CH 2 COOH CH 2 COOH 

Acetone dicar- Cyanhydride Citric acid 

boxylic acid of citric acid 

LACTIC ACID 

Lactic acid, from (lac = milk) is but little used in medicine. 
It is somewhat used as a local application to tuberculosis ulcers 
of the nose and throat, especially on the larynx. 
CH 3 

Lactic acid CHOH is of interest because of its relation to acetic 

I 

COOH 

and formic acid and to glucose and amino acids derived from 
protein. It is formed in the stomach in all fermentations 
and dyspepsias when it may reach 0.4 per cent. There 
is some doubt whether or not lactic acid exists in the 
normal blood. If is present, however, in all cases where 



LACTIC ACID 75 

there is asphyxiation or reduction of tissue respiration and in 
such cases appears in the urine. It occurs especially after 
poisoning with phosphorus, arsenic, hydrazines, chloroform, etc., 
i.e., after those poisons which act on the liver causing hyper- 
glycemia, reduction of glycogen, and fatty degeneration. It 
may also occur in the course of diabetes and wasting diseases, 
and is always present in cases of acidosis. Lactic acid since it 
contains an asymmetric C atom exists in dextro, levo, and race- 
mic or inactive forms. It was first discovered by Scheele in 1780, 
who isolated it from sour milk. In the form of sour milk, 
it was advocated by Metschniko-'f but without any sufficient 
reason as a means of prolonging life. Since milk is an important 
vitamin containing food, it per se would be of great benefit in 
deficiency diseases and some of these benefits may have been 
unduly credited to lactic acid. In the destruction of lactic acid 
by bacteria, propionic, acetic and formic acids may be formed: 

CH3 CH3 CH3 H 

I j I C0 2 .H 2 

CHOH CH 2 COOH COOH 

I ! 

COOH COOH 

Lactic propionic acetic formic 

Zinc lactate Zn(C 3 H 5 03)2.3H 2 is the most characteristic salt of 
lactic acid . The acid may be identified by the analysis of this salt . 

HYDROCYANIC ACID 

Hydrocyanic acid is usually -considered with the paraffin acids, 
but it is not a derivative of the paraffins. It is of direct interest 
to the paraffins because it forms addition products with aldehydes 
and ketones. These can be hydrolyzed, enabling the formation 
of a product richer in carbon than the initial e.g. : 
CH3I + KCN = CH 3 CN + KI 

CH 3 CN + 2H 2 = CH3COOHNH3 

The relation of HCN to formic acid is shown by the following : 
HCN + H 2 -^ HCOONH4 (ammonium formate) 
It is, therefore, the nitril of formic acid. Hydrocyanic acid 2 
per cent., dilute hydrocyanic, is used in medicine as an antemetic 
and in cough mixtures, as a depressant of .the respiratory centre. 
On account of the readiness with which it decomposes, it is not so 



76 CHEMICAL PHAEMACOLOGY 

much used as formerly. It also exists in wild cherry, in amygdalin, 
in KCN, Hg(CN) 2 and other compounds used more or less. 

Because of its toxic action this drug is falling into disuse 
It is of considerable importance in toxicology. It is absorbed 
even from the skin. It is toxic to all ferments and tissues. It 
first stimulates then paralyzes the central nervous system. The 
peripheral muscles and nerves are weakened and eventually para- 
lyzed. The tissues cannot use oxygen and soon die from asphyxia. 
In such cases lactic acid may be found in the blood and urine. 
The oxidative processes of the blood are also checked and the color 
of the blood is bright red due to oxyhemoglobin as is to the fact 
that the tissues from internal asphyxia cannot take oxygen from 
the blood. Whether or not such a compound as cyanhemoglobin 
is formed is still disputed. It is probably formed and readily 
decomposed, though it is harder to reduce than oxyhemoglobin. 

Hydrocyanic acid, if it does not kill is changed to sulphocy- 
anides in the tissues. This seems to be a simple chemical process 
which occurs without the action of living protoplasm. The 
sulphocyanate test for hydrocyanic test is based on this fact. It 
is as follows: 

To a dilute solution of hydrocyanic acid, or a distillate sus- 
pected of containing it, add a few drops of a solution of potassium 
hydroxide, and twice as much yellow ammonium sulphide. 
Evaporate to dryness on a water bath; dissolve in a little water 
and acidify with dilute hydrochloric acid. Filter to remove 
sulphur. If the solution contained hydrocyanic acid the filtrate 
will give a blood red color on the addition of a drop of dilute ferric 
chloride, this is due to the formation of ferric sulphocyanate. 

Hydrocyanic acid occurs in many plants, in the form of 
glucosides — cyanogenetic glucosides. It is present principally 
in the seed, buds, leaves and bark. The cyanide is held to be a 
direct product of photosynthesis, and may be of fundamental 
importance in the metabolism of the plant and perhaps in the 
evolution of life processes. Gautier thinks that prussic acid and 
its compounds may be formed in the plant by the reduction of 
nitrates by formaldehyde. This theory agrees with the distri- 
bution of both nitrates and cyanides in the plant. The amount 
of cyanide in plants varies greatly and may amount to as much 
as 0.3 per cent. In many cases free hydrocyanic will be liberated 



LACTIC ACID 77 

from such plants on chewing — owing to digestion of the glucoside 
— and can be detected in this way. 

To isolate hydrocyanic acid from a plant or tissue : digest the 
finely pulverized substance mixed with water in an incubator or 
on a water bath for two hours at a temperature of 40°C. If the 
temperature is raised much above this, it will kill the ferment and 
prevent the setting free of HCN. Acidify the digest with tar- 
taric acid and distil with steam. Test the distillate by: 

1. Prussian Blue Test. — Add a trace of KOH, then a few drops 
of freshly prepared ferrous sulphate solution and a drop of dilute 
ferric chloride solution. Shake well and warm gently. Finally 
acidify with dilute hydrochloric acid. A blue color is formed at 
once if the quantity of HCN is considerable, if only a minute 
amount is present a bluish green color only develops. 

2. Hydrocyanic acid gives a white precipitate with AgN0 3 . 

3. Vortmann's Nitro-prusside Test. — To a dilute solution of 
hydrocyanic acid add a few drops of potassium nitrate solution, 
then a few drops of ferric chloride and enough dilute sulphuric 
acid to give a yellow color. Heat to boiling and add enough 
ammonium hydroxide to remove excess of iron, filter, and add a 
few drops of very dilute ammonium sulphide. A violet color 
passing through blue green and yellow, indicates hydrocyanic 
acid. It is due to the conversion of the cyanide into potassiura 
nitro-prusside — K 2 Fe (NO) (CN) 5 which changes color when 
ammonium sulphide is added. 

Picric Acid Test. — When a solution of hydrocyanic acid is 
made alkaline with KOH and heated in a water bath at 50°-60°C. 
with a few drops of picric acid, it gives a blood red color due to 
the formation of potassium isopurpurate — C8H 4 N 5 6 K. Sul- 
phides present in decomposing organic matter will also give 
this test and sugars under similar conditions will give a red 
color due to the formation of picramic acid — which is 2 amino 3, 
4, di-nitro phenol C 6 H 2 (NH 2 ).(N02)2.0H. This last is the basis 
of Benedict's method for the estimation of blood sugar. 

Isopurpuric acid does not exist in the free state, but only as the 
potassium salt. Nietzki and Petri (Ber d. deutsch. Chem. 
Gesellschaft 1900-33-1788)— think isopurpuric acid (CgHgOeNs) 
is dicyano-picraminic acid = 5 oxy. 6 amino — 2, 4 di nitro 
isopht halic nitrile : see page 98. 



78 CHEMICAL PHARMACOLOGY 

Purpuric* acid, the formula of which is not definitely known, is 
of biological interest in that its ammonium salt, 

C 8 H4(NH 4 )N 5 06 + H 2 is the dye stuff murexide. The 
murexide test is given by uric acid, caffeine, xanthine, theobro- 
mine and many nuclein bases (see p. 288). 

GENERAL PHARMACOLOGY OF THE ACIDS 

The introduction of COOH into the Marsh Gas series gives 
rise to acids with relatively slight toxicity. The anesthetic 
action of the alkyl radicals is lessened by combination with car- 
boxyl. The introduction of carboxyl into the aromatic series 
lessens the toxicity of the benzyl group. In addition to the car- 
boxyl group the acyl groups exert an action. Acetyl salicylic 
acid is more effective as an antipyretic and analgesic than is 
salicylic acid. Acetyl atoxyl is said to be less toxic than atoxyl. 

The replacement of the hydrogen of the amino group in para- 

mino phenol with an acetyl group, HO<(^ \N t H.COCH 3 



lessens the toxicity, and gives a compound with greater anti- 
neuralgic properties. 

Lactyl phenetidine (lactophenin) 



C 2 H 5 < > NH— CO— CH— CH: 




OH 

is more soluble, and has a less antipyretic action than phenacetin. 
Ecogonine-methyl ester has no anesthetic action but its benzoyl 
derivative, cocaine is noted for its local anesthetic effect. Most 
artificial cocaines contain the benzoyl group. The toxicity of 
aconitine is closely related to the benzoyl and acetyl groups present 
in the alkaloid. The mechanism of the action of these and many 
other similar compounds is little understood, but the total 
action in each case seems to be the algebraic sum of the actions 
of the component chemical groups of the drug. In addition 
1o these there is a molecular action and a hydrogen ion action. 
For the effects of the hydrogen ion, see acidosis, p. 350; see also 
amino acids, p. 304. 



IODOFORM 79 

VIII. IODOFORM AND PHYSIOLOGICAL SUBSTITUTES 

Iodoform, or triodomethane, was the first solid antiseptic known. 
It is prepared by the action of iodine upon alcohol or acetone, in 
the presence of an alkali or an alkaline carbonate. Its formation 
is also used to test for the presence of alcohol or acetone. A solu- 
tion of I in KI is added to the solution of alcohol, or acetone, and 
warmed, then dilute NaOH or KOH is added, drop by drop 
until the color has disappeared. Iodoform is formed : 

CH3COCH3 + 3KIO = CH3COCI3 + 3KOH 
CH3COCI3 + KOH = CH3COOK + CHI3 

The potassium hypoiodite KIO is formed when dilute KOH 
is added to the I in KI solution : 2 KOH + 21 -> KIO + KI + H 2 0. 
The hypoiodites are easily decomposed into iodides, and iodates : 
3 KIO = KIO3 + 2KI. Both the iodate and iodide are usually 
formed in the solution with the iodoform, even when KI has 
not been added. Strong alkalies cause the formation of the io- 
date; and, therefore, if a too strong alkali is added, it interferes 
with the reaction. For this reason, sodium carbonate or potas- 
sium carbonate instead of the hydrate is sometimes recommended 
in making the iodoform test. From alcohol, iodoform is pre- 
pared, possibly according to the following reaction : 

C 2 H50H+I 8 +6KHC03-CHl3 + 5KI + KCOOH + 6C02+5H 2 

Ethyl iodide, acetic ether, and other compounds are probably 
also produced. The result appears to be greatly influenced by 
the temperature, and the relative amounts of the materials used. 
Iodine is an oxidizing agent and the probable mechanism is: 

C2H5OH + O = CH 3 C/ + H a O 

X H 

o 

CH 3 C/ + Je = CI 3 C<f + 3HI 
X H X H 

J) 
CI3C/ + KOH = CHIg + KCOOH 
X H 

Iodoform melts at about 115°C. It is nearly insoluble in 
water, but soluble in alcohol, glycerine, carbon bisulphide, ether 



80 CHEMICAL PHAKMACOLOGY 

and in fats. In medicine it is sometimes used in the form of 
an ointment. 

It is volatile at ordinary temperatures and distils readily in 
steam. When it is suspected in organic matter, and its separa- 
tion is desired, acidify with tartaric acid and distil with steam. 
Extract the distillate with ether and evaporate the ether in a 
suitable dish. Iodoform remains as yellow hexagonal plates 
with a characteristic odor. 

Tests: Lustgarten's. — In a test tube warm a little iodoform 
solution in alcohol with a few drops of sodium phenolate — made 
by dissolving 2 parts of phenol, 4 parts of sodium hydroxide and 
7 of water. A red precipitate is formed which settles to the bot- 
tom. Pour off the supernatant fluid and dissolve the precipi- 
tate in dilute alcohol — a carmine red color results. 

Phenylisocyanide Test. — Add a few drops of aniline to a little 
iodoform solution in alcohol, then a few drops of alcoholic KOH 
solution. When heated gently, phenylisocyanide — C 6 H 5 NC is 
produced. This is recognized by its very characteristic and 
repulsive odor. For reaction see page 43. 

Iodoform is sometimes used as a disinfecting dusting powder, 
and any action it has is due to the liberation of iodine. It has 
two serious disadvantages : 

1. Its disagreeable and persistent odor. 

2. In cases of abraded surfaces, sufficient may be absorbed to 
produce toxic symptoms. For these reasons its use is becoming 
restricted. 

Various other iodine compounds have been devised, with the 
idea of securing the iodine effect, without the disadvantages of 
iodoform. The following are the most common: 

Aristol, or dithymol-di-iodide. 

The stearoptene, thymol, from oil of thyme has the formula : 

CH 3 



OH 



CH 

/\ 
CH3 CH3 



IODINE COMPOUNDS 81 

It is a solid crystalline body, which is used in medicine, especially 
in the treatment of hook-worm disease. It has also been much 
used in biological chemistry as a preservative for urine and other 
fluids. Since it combines with iodine-also an antiseptic — it was 
thought that a valuable iodine compound could be obtained 
without the disadvantages of iodoform. Eichkoff in 1890 pre- 
pared aristol or thymol iodide by the action of iodine on thymol 
in alkaline solution. 

•C3H7 
CeH^r - CH3 
X)I 

C 6 H 2 ^OI 
VCH 3 
X C 3 H 7 

This is a chocolate colored powder and contains about 45 per 
cent, iodine. It has been used as a dusting powder especially 
in soft ulcers, eczema, psoriasis, lupus, burns, infections of ear, 
nose and throat and in many other cases where the odor of iodo- 
form has been a drawback. Its action is similar to iodoform, 
and its only advantage is that it is odorless. 

ElJROPHEN-OR-DI-ISO-BUTYL ORTHOCRESOL IODIDE. 

This is analogous to thymol iodide. It has the formula: 

•C4H9 

C6H2~CH3 

X>I 

C6H2— CH3 

X C 4 H 9 
and is a condensation product of two molecules of isobutyl-ortho 
cresol with one atom of iodine. The action is similar to thymol 
iodide. It contains about 28 per cent, iodine. 

IODOL OR TETRAIODO PYRROL. 

I.C — C.I 

II II 

I.CvyC.1 

NH 



82 



CHEMICAL PHARMACOLOGY 



was one of the first iodoform substitutes. It is prepared by the 
action of iodine on alkaline solutions of pjTrol or indirectly by 
the action of KI on tetrachlor-pyrrol. 

C4H4NH + 8C1 = C4CI44NH + 4HC1 

pyrrol tetra-chlor-pyrrol 

C4CI4.NH + 4KI = C4I4.NH + 4KC1 

Iodol is a tasteless and odorless powder with an action similar 
to iodoform. 

Besides the above iodine containing bodies, from which iodine 
is liberated readily in the body, others have been prepared, but 
since these do not liberate iodine in the body, they cannot be 
classified as true iodoform substitutes. 

In the iodoform substitutes the iodine is not attached directly 
to the benzene ring but replaces the H of the hydroxyl group. 
In Loretin, 1 oxy, 2-iodo — 4 sulphonic acid, 



S0 2 OH 




4 chlor quinoline 



N and vioform 1, oxy, 2-iodo, 




OH 



and nosophen or tetraiodophenol phthalein C20H10I14O4 and 

.OH 
Losophan — or tri-iodo di-metacresol — C 6 HI.3 (^ 

X CH 3 



IODINE COMPOUNDS 



83 



and sozoiodol (iodo para phenol sulphonic acid) 

C6H 2 l2v 

X S0 2 OH 

the I is attached to the ring. 

Such compounds are practically undecomposed by the body, 
and of little value as antiseptics so far as the iodine content is 
concerned. Thej^ are therefore not real substitutes for 
iodoform. 

All phenols have a high antiseptic value ; and the introduction 
of iodine increases this to some extent. The increase is not 
sufficient to warrant approval. 

Besides the above iodoform substitutes, organic combinations 
of iodine have been prepared for administration internally to take 
the place of potassium iodide. Iodides in the form of potassium 
or sodium are sometimes too rapidly absorbed, cause irritation 
of stomach, skin eruptions and other untoward manifestations. 
Many attempts have been made to avoid these complications by 
combining the iodine with organic substances that will be slowly 
decomposed in the body and slowly absorbed. The combinations 
are usually with protein matter, and the composition in most 
cases is not fixed or definite as in the iodoform substitutes. 

Thyreoglobulin is the normal iodine-containing body of the 
thyroid gland. The active ingredient of this has recently been 
isolated by E. I. Kendall and has the formula: 



C - CH 2 - CH 2 - COOH 




H or thyro-oxy-indole 

Iodo-spongin is the iodine compound of the sponge. 

Iodoalbin is a compound of iodine and blood albumin, con- 
taining approximately 21.5 per cent, of iodine. It passes through 
the stomach unchanged, but is decomposed in the intestine. 

Iodopin is iodized sesame oil. As is well known, unsaturated 



84 CHEMICAL PHAKMACOLOGY 

oils may absorb or add iodine — the iodine number. Two prepa- 
rations of iodopin are on the market — one 10 per cent, and 
one 25 per cent. The action is the same as that of potassium 
iodide, but it is claimed that iodism is less likely to develop. 

Iodocasein is a compound of iodine with milk casein, contain- 
ing about 18 per cent, of iodine, in organic combination. Many 
other such potassium iodide substitutes have been prepared, but 
the principle is the same as the above. 

The supposed or claimed advantage of these organic prepara- 
tions is that iodism is less likely to develop. By iodism is meant 
the untoward symptoms that develop after the prolonged use of 
iodides, the most common being catarrh of the respiratory pass- 
ages and adnexa, bronchitis, salivation, skin eruptions, eczema, 
bullae, pemphigus, purpura, fetid breath, nausea and general 
malaise. A dermatitis resembling ivy poisoning is sometimes 
seen after iodoform has been used. 

The fatal dose of iodoform or its substitutes is not definitely 
known. Barois (Arch, de Med. et de Pharm. Militare, 1890) 
records the death of a woman on the 9th day after the injection 
of 3 grams of iodoform in ether. Gaillard (Bull, de Chirurg., 
1889) records a comatose condition and apparent death (but from 
which recovery took place) after the injection of about 6 grams 
iodoform into an abscess, v. Bonsdorff (Jour. Am. Med. Assoc, 
67, 1916, 1052) reports death due to the use of about 40 cc. of 
10 per cent, iodoform solution, 10 cc. at a time being injected into 
the. pleural cavity in a case of tuberculosis in an alcoholic. The 
death in this case was probably due to other causes. Much larger 
doses than any here recorded have been injected without apparent 
injury. 

The symptoms of poisoning in addition to iodism are diuresis, 
somnolence, hallucinations, delirium, lassitude, diminished re- 
flexes, convulsions, paralysis. As in many cases of poisoning, 
sodium carbonate in 1 gram doses may be beneficial, because of 
its eTect on the acidosis which develops. 

The Fate of Iodoform in the Body 

Iodoform and its substitutes are readily decomposed in the 
alkaline fluids of the body, and the iodine is excreted as iodides. 
Some decomposition takes place when it is used on wounds as 



BROMINE COMPOUNDS 85 

a dusting powder. The iodides formed after the administration 
of iodoform have been found in the saliva, perspiration, bronchial 
secretions, urine and other fluids, just as after the administration 
of potassium iodide. Iodo albuminates are also formed as after 
the use of iodides, and the final excretion of the total iodine as 
sodium or potassium iodide, may be long delayed. 

Some iodide undergoes decomposition in the body and free 
iodine is said to have been found in the stomach. If this were 
absorbed however it must circulate as an albuminous compound 
until converted into the inorganic form in which it is excreted. 
Free iodine has not been demonstrated out of the acid medium 
of the stomach yet many theories which assume its presence, 
have been devised to explain skin eruptions, and the inflam- 
matory reactions of the mucous membranes. 

BROMINE COMPOUNDS 

Combinations of bromine similar to iodine have been pre- 
pared amongst which are bromopin, analogous to iodipin. Sabro- 
mine Ca(C22H4i02Br 2 )2, the dibrombehenate of calcium, has a 
feeble bromide action, because it is stored in the fatty tissues 
and liberated slowly, as valerobromide : 

CH 3x 

^CH.CH.BrCOONa 
CH 3 X 

which is formed by the action of bromine on valerianic acid ; and 
adalin which is bromdiethyl — acetyl urea : 



C2H5 



N )CBrCONHCO.NH 2 



C2H; 



As might be surmised from the ethyl groups of this formula such 
combinations of bromides are nerve depressants. The bro- 
mides are hypnotics, and are used in medicine only to depress 
the central nervous system. They are used for this purpose in 
chorea, epilepsy, and have also been used in seasickness and in 
whooping cough. Since bromides are used to a considerable 
extent, bromism often develops, This in the main is similar to 



86 



CHEMICAL PHARMACOLOGY 



iodism, but the skin eruptions and depression are more pro- 
nounced. Acne is often very troublesome. 

Bromides accumulate in the body; that is, they are not ex- 
creted as rapidly as absorbed. This is partly explained by the 
fact that the body cannot well distinguish between the bromine 
and the chlorine ion, consequently chlorine is excreted and bro- 
mine retained. HBr, is sometimes formed in the stomach in- 
stead of HC1. 

It has been questioned by some whether the depressant effect 
of the bromides is due to the presence of the bromine ion or the 
absence of the chlorine ion. In favor of the view that it is due 
to lessened chloride, it has been found that the depressing action 
of the bromides is more pronounced when the chlorides of the 
diet are diminished and Loeb has found that fish are depressed 
by the administration of bromide, but remain normal if chloride 
also is added. However, large doses of bromides depress animals 
before the chlorides are much diminished so that while poverty 
of chlorides may aid the action of bromides they are not the cause 
of it. Bromides are excreted, in the same manner as the iodides. 

IX. BENZENE OR BENZOL 

Benzene, C 6 H 6 , is derived from coal tar. It is the mother sub- 
stance of a long series of products, many of which are important 
in medicine. Because many of them are odoriferous, the series 
is known as the aromatic series. The formula generally given 
to the compound is that of Kekule : 

CH i 




OH 



The reasons for assigning this formula to it are: 
1. All the hydrogen atoms react the same, hence they must be 
similarly linked. 



BENZENE 



87 



2. It acts like a saturated compound — yet if it were an open 
chain structure, it could be represented only as a highly unsatu- 
rated compound. 

3. Under certain conditions it unites with 6 atoms of bromine 
to form C 6 H 6 Br 6 . If it were an unsaturated compound related 
to hexane, it should unite with eight atoms, since hexane when 
saturated has the formula C 6 Hi 4 Br 6 . Hence it seems to be a 
closed ring. 

4. In favor of this is the fact that when gaseous benzene and 
hydrogen are passed through a heated tube containing finely 
divided nickel, 6 atoms of hydrogen are absorbed and hexamethyl- 
ene is formed. This corresponds with the formula: 



CH 



CH S 




CH 



CH 



+ 6H 



CH 2 
CH 2 



CH 2 
CH 2 



CH 



CH, 



That all the hydrogen atoms in benzene are the same, is sup- 
ported by the following facts : 

1. There is but one mono substitution product of chlorine, 
bromine, NH 2 etc. 

2. The theory calls for 3 possible di-substitution products 
and these are known, and only these, e.g. : 



(1.2 and (1.6) di-substitution products are the same. Also (1.3) 
and (1.5) (1.4) and (2.5) and (3.6) are the same. 



88 



CHEMICAL PHARMACOLOGY 



3. Three tri-substitution products only are found, while more 
would be expected if the H atoms were different. 



adjacent 



symmetric 



asymmetric 



These are all that can be found. 

It should be remembered that the existence of the benzene 
ring is still theoretical yet all the facts so far can best be ex- 
plained on the basis of this theory. 

Benzene is a colorless, highly refractive liquid, B. P. 80.5°C, 
Sp. gr. 0.88 at 20°. It is highly inflammable. In commerce 
it is not pure, being usually mixed with other hydro-carbons 
such as toluene. It is insoluble in water; is a good solvent 
for fats, resins, alkaloids, iodine, and other substances, and is 
broken up only with difficulty. Under certain conditions it will 
yield substitution products. With HNO3 it gives nitrobenzene. 
C 6 H 6 + HNO3 = C 6 H 5 N0 2 + H 2 0. When heated with sul- 
phuric acid, it gives benzene sulphonic acid. In the body it is 
but slightly acted on, passing through for the most part unchanged. 
A slight amount may be oxidized to phenol which is excreted 
combined with sulphuric acid. Benzene has been used to a 
considerable extent of late in the treatment of leukemias as it 
causes a reduction of the number of the leucocytes, the dose being 
from 0.5 to 1 cc, four times a day. Frequent examination of the 
blood is necessary and too great doses or too prolonged use of it 
is decidedly harmful, as it may cause an aplastic anemia. By 
this is meant that, while it reduces the number of leucocytes, it 
also acts on the bonemarrow in a harmful way so that the normal 
production of red cells is lessened or stopped. 

While benzene is relatively inactive chemically, the fact that 
it is volatile and will dissolve lipoids confers on it a pharmacologic 
activity which is due entirely to its physical or solvent action. 



PHENOLS 89 

This action is manifested on the motor side of the nervous system, 
and is stimulating. Members of the methane series act mainly 
on the sensory side and are depressant. 

X. PHENOLS 

1. Phenols (Fr. Phenol, Greek Phaino,— shine. Latin, oleum, 
oil.) Hydroxyl derivatives of the methane series are known as 
alcohols. Hydroxyl derivatives of the benzene series are called 
phenols. Only when the OH is attached directly to a carbon 
atom of the ring does the term phenol apply. 

2. Since all the H atoms of benzene are the same, only one 
monhydroxy phenol is possible, and only one is known. Phenol 
is obtained from" coal tar, or is made synthetically. It is found in 
small quantities in combination in urine, and is derived from 
protein. 

Phenol is formed from benzene by the action of oxygen in the 
presence of a catalyzer like platinum black or aluminum chloride. 
Small amounts of it are also formed in the human body from 
administered benzene. 

Phenol occurs in colorless deliquescent prisms which melt at 
42°C. and turn to pink or brown on standing. It boils at 183°C. 
and is volatile in steam. One gram of phenol dissolves in 15 cc. 
of water at 25°C. It is very soluble in alcohol, glycerine, chloro- 
form, ether, carbon disulphide or in fixed or volatile oils. A 
water solution is faintly acid to litmus. When heated phenol 
crystals melt, forming a highly refractive liquid. 

Its solubility is peculiar. When 10 per cent, of water is 
added to phenol it liquefies. This is known as phenol liquefra- 
tum, and may be regarded as a solution of water in phenol. If 
more water be added the solution is destroyed and a clear solution 
is not obtained until 15 cc. of water is added for each gram of 
phenol. This may be considered as a solution of phenol in water. 

Phenol gives a violet coloration, phenolic reaction, with ferric 
salts, and a pale yellow precipitate (of tri-bromphenol 
CeH2Br 3 OH) with bromine water. 

It is a strong germicide, a general protoplasm poison, and is 
excreted from the body mainly as phenyl sulphuric acid or 
conjugated sulphate. 



90 



CHEMICAL PHARMACOLOGY 



It is used in medicine mainly for its antiseptic action, and forms 
the basis of many synthetic drugs whose actions are antiseptic 
and antipyretic. As pointed out under iodoform substitutes, 
iodine when attached to the benzene ring is not decomposed in 
the body. All phenols are antiseptic but the addition of iodine 
increases the antiseptic action. This is the basis for the large 
number of iodine compounds on the market. 

Properties of Phenols 

The phenols have acid properties, but they are weaker than 
carbonic acid hence they are not soluble in sodium carbonate and 
will not decompose carbonates. Sodium phenolate is not formed 
by sodium carbonate but by the use of NaOH. Phenols which 
contain strongly negative substitute groups may be sufficiently 
acid to decompose carbonates. Picricacid for example, which is 
trinitro phenol, is strongly enough acid to do this. 



C 6 H 



/ 



(N0 2 ); 



OH 



Phenols have alcoholic properties and form ethers, not directly 
as with ordinary alcohols, but by use of alkyl iodides, and sodium 
phenolate : 



+ CH 3 I = 



ONa 



Nal 



OCH- 



Phenyl-methyl-ether 
(anisol) 



R 



Ethers have the general formula ")0. In this formula, (phenvl) 

R' X 
C 6 H 5 = R and (methyl) CH 3 = R' The product is a mixed 
ether. 

The introduction of the OH group into benzene greatly 
increases its reactivity, and accordingly increases its antiseptic 
toxic propertied. The tendency of the aromatic group as a whole 



PHENOLS 91 

is to stimulate the motor side of the central nervous system while 
the paraffin series are depressant. In compounds with a paraffin 
side chain the depressant action usually predominates. The 
local action of phenols is always anesthetic, this explains the 
anodyne action of oil of cloves, eugenol, benzyl alcohol, etc., when 
applied to tooth cavities or injected hypodermically. Increase 
in the number of OH groups in phenols as in the paraffin series, 
lessens the physiological activity. 

In case of poisoning by carbolic acid a part is oxidized in the 
body to the dihydroxy benzenes, pyrocatechol and hydroquinone. 
The dark color of the urine is due to further oxidation of the 
hydroquinone with the formation of quinone products. Normal 
urine contains considerable free sulphate; after carbolic acid 
there is little if any free sulphate, all of it being combined with 
the phenol. If such urine is boiled with a mineral acid the 
ethereal sulphate is decomposed and the sulphate can then be 
precipitated with barium chloride, while the sulphates in the 
body combine in this way with phenol. In cases of phenol 
poisoning, the injection of sulphates helps but little. 

Carbolic acid, in cases of poisoning can be separated from the 
tissues by distillation with steam. Long continued distillation 
is necessary to remove the last traces. In case of a man dying 
15 minutes after taking 15 cc. liquid carbolic acid (Ber. d. Deut. 
Chem. Gesell., 16., 1337 1883), BischofT found 

0.171 gram in stomach and intestine 
0.028 gram in blood 
0.637 gram in liver 
0.200 gram in kidnej^ 
0.314 gram in brain. 

This gives one an idea of how quickly poisons spread through 
the body. 

OH 



Resorcinol, (1.3) or meta dihydroxyphenol, 



is 



92 



CHEMICAL PHAKMACOLOGY 



used mainly for the preparation of eosin, fluorescene, and azo dyes. 
It occurs in certain resins, especially galbanum and asafcetida. 
Heated with sodium, it yields the blue indicator known as lac- 
moid, which turns red with acids. Many other meta and para 
compounds yield resorcinol when fused with KOH. It crystal- 
lizes from water in colorless plates or prisms which melt at 118°C. 
Formerly resorcinol was much used in some of the skin diseases 
and has been injected into the bladder in cystitis and infections 
of the genitourinary tract, but it is irritant and likely to be 
painful if used in this way. At present it is not much used in 
medicine. 

Quinol or hydroquinone or para dihydroxy benzene (1.4) is 
named because it can be obtained from quinone by reduction 
with sulphur dioxide and water. 




OlT 



+ S0 2 + 



H.OH 



H.OH 



+ H 2 S0 4 



OH 

Hydroquinone 

It was first obtained by the dry distillation of quinic acid : 
C 6 H 7 (OH) 4 COOH + O = C 6 H 4 (OH) 2 + C0 2 + 3H 2 

It occurs in nature in combination as a glucoside arbutin, and 
uncombined in some leaves and flowers (vaccinum vitis idcea). 
The form is colorless and crystalline and melts at 170°C. This 
substance has been used as an antipyretic but has been super- 
seded by the modern antipyretics. 



DIHYDROXY PHENOLS OR DIHYDROXY BENZENES 

Three di-hydroxy phenols are theoretically possible, and all are 
known and can be prepared from plants. They are, catechol 
(1.2), resorcinol (1.3) and hydro-quinone (1.4). 



DIHYDEOXY BENZENES 



93 



Catechol, pyrocatechol or pyrocatechin or 1.2 hydroxy benzene 
occurs in beech-tar. 

OH 



OH 



As the name indicates, (pyros-fire), it is derived from the de- 
structive distillation of catechu, which contains protocatechuic 
acid : — 

OH OH 



OH 



COOH 



OH 



CO ; 



+ 



It crystallizes in colorless prisms from benzene, and melts at 
104°C. It can also be prepared by fusing phenol sulphonic acid 
withKOH: 



OH 



OH 



S0 3 H + KOH 



OH KHSO; 

+ 



It occurs in small amounts combined with sulphuric acid in the 
urine of horses and human beings. It is also found in many tan- 
nins — the pyrocatechol tannins, especially those of pine and oak 
barks (not in oak galls), acacia, cutch, and gambir. 

Pyrocatechol has met with little use in medicine. It was 
formerly used as an antipyretic, but it is toxic and forms methe- 
moglobin readily. This is the parent substance from which 
synthetic adrenalin or epinephrine is derived, and itself produces 



94 



CHEMICAL PHAKMACOLOGY 



an appreciable rise of blood-pressure. Epinephrine is derived 
from catechol according to the formula given under epinephrine 
(p. 236). 

TRIHYDROXY BENZENES OR TRIHYDRIC PHENOLS 

I Pyrogallol or pyrogallic acid, 1.2.3, is so-called because it 
is formed from gallic acid C 6 H 2 (OH) 3 COOH (1.2.3.5) by heating. 



OH 



COOH 



OH 
OH 



OH 




OH 



CO, 



+ 



gallic acid 



pyrogallol 



It is also formed by fusing hemotoxylin with KOH. Its 
dimethyl ether is found in beechwood creosote. Pyrogallol is 
the best known member of the trihydric phenols. It crystallizes 
in colorless plates which melt at 132°C. In excess of caustic 
alkali it absorbs oxygen readily and is employed in gas analysis 
for this purpose. It is used in certain skin diseases and in hair 
dyes. 

II Phloroglucinol, 1.3.5, trihydroxy benzene, was first 
obtained from the glucoside phlorizin. It is also found in the 
glucosides, quercitin and hesperidin, and can be produced by 
fusing catechu, kino and other resins with KOH. It can be 
formed from resorcinol, which illustrates a frequent reaction that 
takes place on fusion with alkalies, namely, the replacement of 
hydrogen by hydroxy!: 

OH 



OH + = OHk 
Resorcinol — > phloroglucinol. 




CRESOLS 



95 



Phloroglucinol is a white crystalline body that melts at 219°C. 
and tastes sweet. It is not used in medicine but is used in chemis- 
try as a reagent with HC1 to detect galactose, pentose, or 
glycuronic acid. These give a red color when heated with an 
equal volume of HC1 specific gravity 1.09 and a little phloroglu- 
cinol is added (Tollen's reaction). 

Gallic acid and tannic acid are phenols. 



OH 



Gallic acid 



OH 



OH 




COOH 



on heating gives pyrogallol — see formula p. 94. 
Tannic acid is digallic acid. 



CO 



OH 



OH 



HOOC 




OH 



OH 



OH 



The tannins are sometimes divided into the pyrogallol and the 
catechol varieties, according to the color they give with ferric 
salts. The pyrogallol group gives a dark blue, and the catechol 
group gives a greenish color (see tannins). 



CRESOLS 

Cresols (cresote + ol) are methyl phenols, 
cresols; ortho, meta, and para. 



There are three 



96 



CH ; 



CHEMICAL PHARMACOLOGY 
CH 3 



CH; 



OH 



OH 



OH 
Ortho Meta Para 

They occur in the distillate from coal tar and the tars from pine 
and beech wood. Like phenols, they react with ferric chloride 
to give colored solutions, and with bromine to give precipitates. 
They are readily nitrated. 

- Creosote from beechwood tar consists chiefly of a mixture of 
phenols, cresols, and guaiacols. 



Guaiacol, 



OCH; 



so called because it was first obtained 



OH 



from guaiac resin, is the mono-methyl-ether of pyrocatechin. It 
possesses both the properties of an ether and a phenol, gives a 
methyl green color with iron salts and is converted into anisol or 
phenyl methyl ether on reduction with Zn. 



OCH, 



OCH, 



Anisol 



Veratrol 



OCH; 



is the dimethyl ether of pyrocatechin 



and is prepared from the seeds of sabadilla officinalis. 



PICRIC ACID 97 

Creosote (Gr. Kreas, flesh; Soter, preserver) is a mixture of 
phenols and cresols and guaiacols, obtained during the distillation 
of wood tar. 

Creosotum, owing to the presence of phenols, has much the 
same action as phenol itself. Due to its anesthetic properties, 
creosote on cotton is sometimes inserted in a cavity to allay the 
pain of toothache. In addition, it possesses caustic and antisep- 
tic properties. Many derivatives, based on the salol principle 
(q.v.) have been introduced, as intestinal antiseptics. 

Creosote carbonate is one of these. It is a mixture of the 
carbonates of the various constituents of creosote, chiefly guaiacol 
andcreosol. The formation of this ester greatly lessens the toxi- 
city and caustic action of the original mixture, which is said to 
be less toxic and more powerfully antiseptic than phenol. It is 
a tasteless, odorless powder, well borne by the stomach. 

Picric acid or tri-nitro-phenol is the most important nitrophenol 
derivative. The introduction of the nitro group into phenols 
increases the antiseptic and toxic action. 

It is a powerful blood poison, renal irritant and respiratory and 
cardiac depressant. The introduction of the nitro groups also 
increases the acidity of the phenols. Phenol will not decompose 
sodium carbonate but picric acid will. Sodium phenolate is 
formed in the reaction, while only by the action of NaOH is it 
formed from phenol. The prolonged consumption of small 
quantities of picrate colors first the conjunctiva of the eyes, but 
later the entire skin may become yellow. This may be mistaken 
for jaundice. Picric acid is changed to picramic acid in the 
body, and this colors the urine red. Some is excreted unchanged 
in the urine and feces. It produces anuria, strangury, vomiting 
and may cause convulsions, like phenol. The red color of pic- 
ramic acid has been utilized by Benedict and others as a 
method for the quantitative determination of glucose, and the 
reaction in the body is probably with glucose. The picramic 
acid is not so toxic as picric. 

Tests for Picric Acid 

I. The material or solution containing it in yellow aqueous, 
alcoholic or ethereal solutions have the same color. It is easily 
extracted with ether; and is somewhat soluble in water. The 
tests are made in water solution. 

7 



98 CHEMICAL PHARMACOLOGY 

II. It dyes a thread of cotton, wool or silk yellow. 

III. A solution of picric acid warmed to 60°C. with a few drops 
of KCN gives a red color due to the formation of isopurpuric acid. 
This acid does not exist in the free state but is present in this 
test as the K salt. The formulas assigned to isopurpuric 
acid are 

OH OH 

I I 

C C 

• \ / \ 

2 N— C C— NH 2 2 N— C C— NHOH 

! I I ! 

NO-C C— CN NO- C C— CN 

V/ • \/ 

c c 

I I 

N0 2 N0 2 

Nietzki-Petri Borsche 

IV. When picric acid is made alkaline with'a solution of sodium 
carbonate and a trace of glucose added (1 cc. 0.1 per cent.) and 
heated on a water bath or over a free flame a red color due to 
picramic acid is developed. This has the formula — 

OH OH 

! ! 

c c 

y\ y\ 

2 N— C6 2O-NO2 2 N— C 6 O-NH2 

I + 6H = I J + 2H 2 

HC CH HC CH 

\4/ \4/ 

C C 

I I 

N0 2 NO2 

Picric acid Picraminic acid or picramic acid. 

This color is very similar to that of isopurpuric acid. 
Reactions of the Phenols 

1. Practically all phenols give a color reaction with Fe 2 Cl 6 
varying from greenish to violet. This reaction is known as the 



REACTIONS OF THE PHENOLS 99 

phenolic reaction. For this reason, phenols are incompatible 
with iron salts. (Hydro quinone does not give a color with iron, 
which oxidizes it to quinone.) 

2. All phenols give Liebermann's reaction: when a phenol 
is treated with sulphuric acid and a nitroso compound or a nitrite 
is added, it yields colored solutions. When the solution is 
treated with an excess of alkali, it assumes an intense blue or 
green color: 

3. Pyrocatechol, pyrogallol, and phloroglucinol are precipi- 
tated with lead acetate. Resorcinol and hydroquinone are not. 
(a) They all reduce Fehling's solution on warming. 

4. Nearly all phenols reduce ammoniacal solutions of silver 
nitrate and salts of mercury and gold to their respective metals. 

5. Generally, phenols react with an aqueous solution of NaOH 
to form soluble salts, but they are insoluble in Na2C0 3 . 

6. With bromine water, most phenols yield a precipitate of 
brominated phenol. The most important reactions are those 
with alkalies, ferric chloride and bromine water, and Lieber- 
mann's reaction. The fact that phenol gives CeKUONa, sodium 
phenolate with NaOH, but is too weak to decompose sodium 
carbonate, distinguishes phenols from acids. 

When taken into the body, the phenols are combined and 
excreted with sulphuric acid, glycuronic acid, etc. Yet phenol, 
when heated in a test tube with sulphuric acid, is not changed to 
any extent, because it is less basic than alcohol and does not 
form salts so easily. 

7. All monhydric phenols give Millon's test. When heated 
with Millon's reagent (A solution of mercuric nitrate containing 
free HN0 3 ) a red color is produced. 

Like the alcohols, phenols contain an hydroxyl group, and 
reagents which act on the hydroxyl will act on a phenol : 

C 6 H 5 OH + CH3COCI = CH 3 C0.0 6 C 5 H + HC1 

acetyl chloride 
C 6 H 5 OH + PCI5 = C 6 H 5 C1 + POCI3 + HC1 

C 6 H 5 GH + Na = C 6 H 5 ONa + H 

Phenols also form ethereal salts or esters which are decomposed 
only in alkaline solutions. The irritating action on the stomach 
of one or both components of such salt can be avoided in this way 



100 



CHEMICAL PHARMACOLOGY 



and the antiseptic effect retained. This is an important reaction 
in medicine; the Nencki salol principle is based on this fact. The 
principle is this: To get the antiseptic effect of the phenols, or 
derivatives in the intestine or genito-urinary tract, they cannot 
be used as such because they are caustic and irritating to the 
stomach. In the form of their ethereal salts they pass through 
the stomach unchanged but in the neutral reaction of the intes- 
tine, these salts are slowly decomposed into their components. 
The physiological action of the components is therefore obtained 
and the irritation of the stomach avoided. Since Nencki was 
the first who used salol with this idea in mind, the principle when 
used with any combination is known as Nencki's salol principle: 

C 6 H 5 (OC.C 6 H 4 OH) + H 2 = C 6 H 5 OH + C 6 H 4 OHCOOH 
Phenol salicylate (salol) Phenol Salicylic acid. 

The phenols correspond to tertiary alcohols since they yield 
neither aldehydes nor acids on oxidation. When, they have 
paraffin side chains, these side chains may be oxidized and yield 
the same alcohol aldehydes and acids as when they are free: e.g., 
when oxidized with chromyl chloride Cr0 2 Cl 2 : 



O 



CH 




CH 2 OH 



\ 



H 



COOH 



Toluene Benzyl alcohol Benzaldehyde Benzoic acid. 

Toluene can be regarded either as methyl benzene or phenyl 
methane — 

H 
H — C — CeH 5 
H 



AROMATIC ALCOHOLS 



101 



It is a colorless liquid which boils at 110°C. It is used as a 
laboratory antiseptic especially to prevent the growth of bacteria 
when the action of ferments is to be determined. It has rela- 
tively little action on ferments. It is of direct interest in medi- 
cine only as a source of other drugs, such as benzyl alcohol, 
benzaldehyde and benzoic acid. Toluene can be oxidized in the 
body to benzoic acid and is excreted combined with glycocoll 
as hippuric acid (q.v.). 

Friedel and Craft's Reaction for Toluene Synthesis. — When 
benzene is treated with methyl chloride in the presence of alumi- 
num chloride, which acts as a catalyzer, toluene is formed 
according to the following reaction: 



+ CH3CI = 



+ HC1 



CH, 



Toluene is also formed by the dry distillation of balsam of tolu 
or by distilling toluic acid with lime 

C 6 H 4 (CH 3 )COOH = C 6 H 5 CH 3 + C0 2 . 



XI. AROMATIC ALCOHOLS, AND PHENOL ALCOHOLS 

When a benzene compound contains an hydroxyl group in a 
side chain it is known as an aromatic alcohol. There may also 
be mixed compounds in which both phenol and alcoholic groups 
are present, e. g.\ 

1. Benzyl alcohol or phenyl carbinol 



C 6 H 5 CH 2 OH or 



CH 2 OH 



is a type of the aromatic alcohols; while 



102 CHEMICAL PHARMACOLOGY 

2. Saligenin or salicyl alcohol 



OH 



C 6 H 4 OHCH 2 OH or 



CH 2 OH 



is both a phenol and an aromatic alcohol. 

Benzyl alcohol has recently come into vogue as a local anes- 
thetic, and benzyl benzoate has been advised in a variety of 
internal conditions thought to be due to a spasmodic condition of 
smooth muscle. It undoubtedly has some local action, but it 
will take some time to evaluate it as a therapeutic agent. It- 
has the general properties of alcohols. 

Saligenin. — Saligenin is found in willow bark in the glucoside 
salicin which is a combination of saligenin and glucose (p. 193). 
It can be prepared synthetically by the action of formaldehyde 
on phenol — 



+ HC 



y 







OH 



H 



CH 2 .OH 
OH 



Saligenin is oxidized in the body to salicylic acid. Like all 
phenols it has anesthetic properties. 

Cinnamyl alcohol, C 6 H 5 CH:CH.CH 2 OH, is another phenol 
alcohol, but it differs from benzjd alcohol in that the side chain is 
unsaturated. It is a crystalline substance with the odor of 
hyacinths, and is present as an ester in the resin storax. It can 
also be prepared by heating benzaldehyde and sodium acetate 
together, in presence of a dehydrating agent, 



CeHs — CH 

benzaldehyde 



O + H 2 CH 



-COONa 
sodium acetate 
= C 6 H 5 — CH = CH — 



-COONa 



ALDEHYDES OF THE AROMATIC SERIES 



103 



It is not used as a medicine, but the aldehyde is added to per- 
fumes to give the odor of cinnamon. Other aromatic alde- 
hydes used in perfumes are: 

Citral or geranial . . . which gives the odor of lemon — 

(CH3)2C:CH.CH 2 .CH 2 .C(CH 3 ):CH.CHO 
Vanillin , . . which gives the odor of vanilla — 

,CHO 1 

C6H 3 ^— OCH 3 3 

X OH 4 

Piperonal . . . which is related to vanillin and coumarin — 

CHO 1 



C6H 3s - — (X 3 

\ >CH 2 

(X 4 

It possesses the odor of heliotrope to a remarkable degree. In 
commerce it is known as heliotropin. 

ALDEHYDES OF THE AROMATIC SERIES 

Benzaldehyde is found in bitter almonds as the glucoside 
amygdalin : 

C 2 oH 27 NOii + 2H 2 = 6C 6 H 12 6 + HCN + C 6 H 5 CHO 
amygdalin glucose benzaldehyde 

Benzaldehyde also occurs in ester combination with benzoic 
and cinnamic acid in balsam of tolu, peru, and in storax. 
Salicylic aldehyde — 

- Saligenin + = Salicylic aldehyde 



OH 
CH 2 OH + O 



OH 

//° 
Cf + H 2 

X H 



The free aldehyde occurs in the essential oil of spiroea ulmaria 
and in the blossoms of meadow sweet and other volatile oils. 



104 CHEMICAL PHARMACOLOGY 

It is a fragrant colorless liquid B.P. 196° C, which is readily 
oxidized to salicylic acid. 



OH 

COOH 



In the body each of these aldehydes is oxidized to the correspond- 
ing acid. 

KETONES OF THE AROMATIC SERIES 

The only aromatic ketone used to any extent in medicine is 
aceto phenone, or hypnone or phenyl methyl ketone, C 6 H 5 CO.CH 3 . 
It has fairly strong hypnotic properties, due to the methjd group, 
but the action is more powerful and possesses no advantages 
over the well known hypnotics of the aliphatic series. 

Phenyl ethyl ketone, C 6 H 5 CO.C 2 H5, has a more powerful 
action than acetophenone but less than the aliphatic series. It 
also is oxidized in the body to benzoic acid. 

Benzo phenone, C 6 H 5 :CO.C 6 H5, has slight hypnotic properties, 
but much less than that of the aliphatic ketones. 

When fused with KOH it breaks down into benzoic acid and 
benzene and we should expect this reaction to take place to some 
extent in the body. 

XII. ACIDS AND RELATED COMPOUNDS 

Benzoic Acid. — Benzoic acid, C 6 H 5 COOH, is readily prepared 
by oxidation of benzaldehyde. It is found in gum benzoin and 
in all balsams. Crystallization takes place from hot water in 
glistening flat plates or needles which melt at 120 o -121°C. It 
reacts readily with alkali hydrates and carbonates to form benzo- 
ates. Benzoic acid or the benzoates have very little toxicity. 
They are not much used in medicine at the present time, having 
been superseded by the salicylates. 

When taken into the body, benzoic acid combines with glyco- 
coll (amino acetic acid) to form hippuric acid, and is excreted as 



ACIDS AND RELATED COMPOUNDS 105 

such C 6 H 5 COOH + H2N.CH2COOH = C 6 H 5 CO.HN.CH 2 COOH 
(hippuric acid). 

Salicylic acid is the most important hydroxy benzoic acid in 
materia medica. It occurs as the methyl ester in the oil of 
wintergreen (oleum gaultheria) and in the oil of birch (oleum 
betulse). 

There are some of the free acids in these oils, and also in the 
buds of spiraea ulmaria. It can be prepared by the action of 
C0 2 on sodium phenate at 200°C. 

X)H 
2C 6 H 5 ONa + C0 2 = C 6 h/ + C 6 H 5 OH 

X COOH 

Salicylic acid is a strong antiseptic and has been used in the 
preservation of food, wines, beer, etc. 

OH 

COONa 



Sodium salicylate is a frequent remedy in the treatment of 
acute rheumatism. Its derivatives, salol, and aspirin, are used 
for the same purpose. 

It was formerly believed that the synthetic salicylic acid 
possessed toxic properties and should not be used in medicine. 
Recent investigation has shown, however, that the natural and 
synthetic salicylates are identical in *K ->peutic action. The 
earlier toxic action was due to impurities. 

When the carboxyl (COOH) group is introduced into the 
phenol-nucleus, the action of the phenol is greatly modified, 
and the toxicity lessened. The extent of the change, however, 
depends on the relation of the OH and COOH in the ring. If 
they are in the ortho (1 : 2) position, as in ordinary salicylic acid, 
the antiseptic power is about the same as phenol and the anti- 
pyretic action is greatly increased. The 1:3 and 1:4 oxybenzoic 



106 



CHEMICAL PHARMACOLOGY 



acids are neither antiseptic nor antipyretic in action. Also the 
introduction of a methyl group in place of the hydroxyl hydrogen 



As in ortho-methoxy benzoic acid 



OCH, 
COOH 



greatly lessens the antiseptic and antipyretic action, just as 
methoxy quinine is less antipyretic than quinine. 

On the other hand, the introduction of the acetyl group, 
CH3CO, as in aspirin, does not cause much change in action, 
and in some respects improves the salicylate as a therapeutic 
agent. 

Aspirin is acetyl salicylic acid and is prepared by the action of 
acetyl chloride on salicylic acid at high temperatures. 



^OH 



+ CH3CO.CI = 



COOH 



OOCCH; 



COOH + HC1 



The stomach tolerates it better than sodium salicylate. 

Salol is phenyl salicylate. It is formed by the action of a 
dehydrating agent like POCl 3 on a mixture of phenol and salicylic 
acid. 

^alde^fc 



OH 



COOIHHO 



OH 



COOCJI5 + H 2 



salicylic 
acid 



phenol 



salol 



MESOTAN 



107 



It is also formed by heating salicylic acid at 200-220°C. 

,OH .OH 

2C 6 H 4 <; = c 6 h/ + H 2 + C0 2 

X COOH X COOC 6 H 5 



Salol is used as an intestinal antiseptic, the action being due 
mainly to the slow liberation of phenol, in the natural alkalinity 
of the intestine. The principle of giving salol to obtain the 
action of phenol and salicylic acid in the intestine without their 
irritating action on the stomach was first used by Nencki and 
is known as Nencki's salol principle (q.v.), p. 100. 

Mesotan or the monomethyl ester of salicylic acid is used to a 
considerable extent in medicine. It is prepared by the action of 
chlor methyl ether on sodium salicylate: 



OH 



COOi. Na 



+ CH 



CI 




OH 

COOCH 2 0. 
CH 3 + NaCl 



Sodium salicylate + Chlormethyl 

ether 



Mesotan 



When used locally in acute rheumatism it may produce derma- 
titis, probably by the irritative action of its hydrolytic products. 
It readily undergoes hydrolysis as follows : 

O 
,OH .OH # 



C6H4 



\ 



+ H 2 = C 6 H, 



+ HC+CH3OH 



OOCH 2 O.CH ; 
Mesotan 



COOH 



H 



salicylic formal- methyl 
acid dehyde alcohol 



Nothing definite can be stated about the form in which the sali- 
cylates are excreted. It was formerly taught that salicylic acid 
combines with amino acetic acid and is excreted as salicyluric 
acid (c/. benzoic acid), Recent work does not substantiate 



108 



CHEMICAL PHARMACOLOGY 



this statement. In the earlier work it is thought that the product 
isolated as salicyluric from the urine was salicylic acid, mixed with 
some impurities. 

Cinnamic acid or phenyl acrylic acid, C 6 H 5 CH:CHCOOH, is of 
interest because many balsams contain it, and it is the most 
important phenyl derivative containing an unsaturated side 
chain. Leucocytosis in experimental animals is caused by the 
use of it, and for this reason it was used for a time in tuberculosis 
with the idea of increasing phagocytosis. The clinical results 
have not shown any benefit. 

It may be prepared by the condensation of benzaldehyde and 
acetic acid or sodium acetate on 



y 



613 CH.COOH = C 6 H 6 CH.CH.COOH + EUO 



CeH 5 Cs 

H -f acetic acid cinnamic acid 

benzaldehyde. 

Balsams are resins or oleoresins that contain cinnamic or 
benzoic acids, or both these acids. The acid or its preparations 
has very few, if any, uses in medicine. 

Phenyl quinoline carbonic acid (atophan) or acidum phenyl 
cinchoninicum or phenyl quinoline carboxylic acid = 2 phenyl 
quinoline 4 carboxylic acid, Ci 6 Hn0 2 N, 

COOH 




C 6 Hj 



melts at 210 c. with partial decomposition. It is insoluble in cold 
water, slightly soluble in cold alcohol, hot alcohol and ether. A 
saturated solution in dilute HC1 gives reddish brown crystals 
with platinic chloride. It is soluble in ammonia from which it is 
precipitated by AgN0 3 or lead acetate. It is used chiefly in 
gout to increase the uric acid elimination. It does not relieve 
the pain and inflammation of an acute attack to the same degree 
as the wine of colchicum, or the alkaloid colchicine. 



ANILINE BODIES 

The ethyl ester of atophan 

COOC 2 H 5 



109 



CfiHj 



N 
is known as acitrin. 

Novatophan is the methyl derivative of acitrin and is the 
trade name for ethyl, 6 methyl phenyl quinolin, 4 carboxylate — 

COOC2H5 



CfiH; 



Its properties and uses are the same as phenyl cinchoninic acid. 





XIII. ANILINE AND TOLUENE DERIVATIVES 

Aniline is the basis of the modern antipyretics. 
When concentrated HN0 3 acts upon benzene, nitrobenzene 
is formed: 

C 6 H 6 + HNO3 = C 6 H 5 .NQ 2 + H 2 

Nitrobenzene is a pleasant smelling colorless oily liquid with 
the odor of bitter almonds, often used to scent soaps, but mainly 
in the manufacture of aniline. It soon darkens on exposure to 
air. Its boiling point is 208°C. It has a strong poisonous action. 
There are on record cases in which from 10-20 drops has caused 
death. It changes the blood to a chocolate color but no meth- 
emoglobin has been found, but a special absorption band between 
C and D (Fihlene's nitrobenzene band) appears. Nitrobenzene 
also causes paralyses of the central nervous system. It is ex- 
creted as glycuronic acid in the urine. Its use in medicine is 



110 



CHEMICAL PHAKMACOLOGY 



limited. When introduced into the body some of it is reduced to 
para-ami no phenol. 

OH 



NH 2 

This compound is of interest because all of the aniline com- 
pounds or antipyretics are supposed to cause a reduction of 
temperature due to the formation of this substance in the body. 

Nitrobenzene on reduction with nascent hydrogen gives aniline. 
This is the characteristic test (see tests for aniline, p. 112): 



N0 8 +-6H = 



NH 2 + 2H 2 



Aniline is moderately toxic in its action and produces hemo- 
globinuria, and an abundance of urobilin. The typical symp- 
toms of aniline poisoning are vertigo, asthenia, gastritis, 
diplopia, and sometimes exfoliative dermatitis. Since the para- 
amino-phenol is less toxic, attempts have been made to use this 
substance as the starting point of synthetic antipyretics, rather 
than aniline. Phenacetin is the result of such research. 

Acetphenetidinum or phenacetin: 

OC 2 H 5 OC 2 H fi 



NH 2 

Aniline 



NH 2 

Phcnetidin 



NHCOCH3 

Acetphenetidin 



ANILINE BODIES 



111 



The following reactions occur in the preparation of phenacetin 
OH OH 



+ HNO'j 



+ H 2 



N0 2 
Phenol Para-nitro-phenol 

There is aiso some ortho nitrophenol formed which can be 
separated from the para by distillation with steam : 
OH ONa 



II. 



III. 



IV. 



+ NaOH 



+ H 2 



N0 2 
ONa 



N0 2 
OC 2 H 5 



+ C 2 H 5 I = 



+ NaI 



NO< 



OC 2 Hi 



N0 2 
This'is reduced with hydrogen 
to phenetidin. 
OC 2 H 5 



,+ CH3COOH 



+ H 2 



NH 2 

Phenetidin 



NHCOCH3 

Paraacetphenetidin or phenacetin 



112 CHEMICAL PHARMACOLOGY 

If aniline be taken internally, it is excreted in combination with 
glycuronic acid as glycuronate, which will reduce Fehling's 
solution. Some aniline may be formed free in the urine. Ani- 
line is a weak base and some of it will distil from acid solution. 
It gives the following tests : 

I. Hypochlorite Test. — To an aqueous solution of aniline 
add a few drops of a filtered solution of bleaching powder or 
sodium hypochlorite drop by drop. A purple-violet color 
changing to red is produced if aniline be present. 

II. Chromic Acid Test. — To a solution of aniline in a porce- 
lain dish add a few drops of concentrated sulphuric acid and a 
few drops of a solution of potassium dichromate. A blue color 
results. 

III. Bromine Water Test. — Bromine water with aniline 
gives a flesh colored precipitate. The test is sensitive to 1 in 
50,000. 

IV. Phenyl Isocyanide Test. — Aniline contains the NH 2 
group and will give the phenyl isocyanide test. 

A few drops of aniline solution with chloroform and KOH, 
when heated, gives the repulsive odor of phenyl isocyanide. 
Acetanilide will also give this test. When acetanilide is boiled 
with KOH or alcoholic KOH it is decomposed into aniline and 
potassium acetate. It will then give the tests for aniline. 

V. Ether or chloroform will extract acetanilide from acid 
aqueous solution. Acetanilide will give the indo-phenol 
test. 

Boil acetanilide with concentrated HC1 and evaporate almost 
to dryness. Cool and add 5 cc. saturated aqueous carbolic acid 
solution, then a few drops of hypochlorite solution. A violet-red 
color is produced. Carefully add a layer of ammonium hydrate; 
this will take on an indigo-blue color. 

Other drugs (phenacetin) give this blue color, which is charac- 
teristic of acetanilide only when preceded by the violet-red 
color. See indo-phenol reactions (Richter's Organic Chem., 
1911, vol. II, p. 173). 

ACETANILIDE 

Acetanilide (antifebrine) is formed when aniline is treated 
with acetyl chloride or acetic anhydride. 



ACETANILIDE 



113 



+ CH3COCI- 



+ HC1 



NIL 



NH.COCH; 



II. The usual method of preparation is by boiling a mixture 
of aniline and acetic acid for some hours : 

C 6 H 5 NH 2 + CH3COOH = C 6 H 5 NH.CO.CH 3 + H 2 

Acetanilide is a colorless crystalline substance which melts 
at 116°C. It is hydrolyzed to its components rather readily. 
This happens in the body, where aniline is converted into para- 
amino phenol, which in greater part is excreted combined with 
sulphuric and glycuronic acids. Some of it is excreted as oxy- 
carbanile, 



:n 



CfiEL 










OH 



These changes reduce the toxicity of aniline. The antipyretic 
action is thought to be due to the paramino-phenol. 

Antipyrine or phenyl dimethylpyrazolon is an antipyretic of 
importance. It is not an aniline derivative, but is more closely 
related to phenyl hydrazine. 

Hydrazine, HN 2 .NH 2 , is a strong base and extremely toxic. 

Phenyl hydrazine, C 6 H 5 NH.NH 2 , is a compound of great 
practical importance and is easily prepared by the reduction of 
diazo-benzene chloride (benzene diazonium chloride) as follows: 

C 6 H 5 .NH 2 + HC1 + HN0 2 = C 6 H 5 N:N.C1 + 2H 2 

Diazo benzene chloride 

When this is reduced with HC1 and stannous chloride 

C 6 H 5 N:N.C1 + 4H = C 6 H 5 NH.NH 2 HC1 

phenyl hydrazine, HC1, is produced which, when treated with 
NaOH, the HC1 is removed as NaCl. The technic of carrying 

8 



114 



CHEMICAL PHARMACOLOGY 



out any of these reactions can be obtained from any book on 
methods in organic chemistry. 

Phenyl hydrazine is a most important reagent for the identifi- 
cation of aldehydes and ketones with which it readily combines 
to form hydrazones and osazones. With beta-diketones and 
/3-ketone esters, it forms ring compounds containing nitrogen, 
the so-called pyrazoles and pyrazolones. 

Phenyl methyl pyrazolone is formed when phenylhydrazine 
is heated with aceto-acetic ether, as follows : 



CH3-CO 

H 2 C - CO - OC 2 H 5 

Aceto-acetic ester 



H 2 N CH 3 - C = K 

+ I )n-c 6 h 5 

HN— C 6 H 5 ->H 2 C— CCK 

+ H 2 + C 2 H 5 OH 
Phenyl Phenyl methyl 

hydrazine pyrazolon 



The name pyrazole comes from pyrrole, a feeble basic body 
found in coal tar and in the dry distillation of bones (pyros, fire; 
oleum, oil); By the introduction of N into this ring, it becomes 
pyrazole. 



CH 



CH 



CHv .CI 

N 
Pyrrole 



CH 

N 



CH 
CH 



NH 

Pyrazole 



Pyrazolon is: 



CH 

N 



CH 2 

c = o 



NH 



PYRAZOLON 115 

1. Phenyl 2.3 dimethyl pyrazolon, or antipyrine, is: 



CH 3 C 



CH 



c = o 



CH 3 N 

C 6 H 5 N 

The pyrazolons or ketohydro pyrazoles are the pyrazole deriva- 
tives known for the longest time and are produced by the 
elimination of alcohol from the hydrazones of /3-ketonic esters. 

Phenyl hydrazone aceto-acetic ester, 1.3 Phenyl methyl 
pyrazolon i(3-ketonic esters, are esters in which the ketone group 
C = O is the j8 position with reference to the COOH group. 
For example, in aceto-acetic ester: 

CH 3 .CO CH 2 COOC 2 H 5 
(ft (a) 
The CO is in the 6, position, and this reacts with phenyl hydra- 
zine to form phenylhydrazone aceto acetic ester: 

CH 3 .C - CH 2 - COOC 2 H 5 . CH 3 .C = CH 2 

\ II I 

N C = 

N- N-C 6 H 5 \/ 

H 2 H NC 6 H 5 

This, on loss of alcohol and water, 
gives, 1 : 3 phenyl methyl pyrazolon. Aceto-acetic ester reacts 
under some conditions as if the constitution were 
CH 3 .C(OH) :CH.COOC 2 H 5 
This last form is known as the "enol" form (alcoholic), the 
other as the " keto " form. By using the enol form, the formation 
of phenyl dimethyl pyrazolon or antipyrine can be more simply 
explained. 
I. CH 3 CH 3 

I , , H x I . 

C.\OH \ )N.HNC 6 H 5 C - NH.HNC 6 H 5 H 2 

11 v y = 11 

CH H + CH 

phenyl hydrazine | 

COOC 2 H 5 COOC 2 H 5 
aceto acetic ester aceto-acetic 

"enol" form hydrazone 



116 



CHEMICAL PHARMACOLOGY 



II. On heating, this loses alcohol and gives: 
CH 3 



-NH 



CH 



co- 



or 1 phenyl. 3 methyl pyrazolon. 



-NC 6 H 5 

When this is treated with methyl iodide antipyrine is formed : 

CH 3 C=CH CH 3 C=CH 

I I I I 

HN CO + CH 3 I = CH 3 N CO + HI 

NC 6 H 5 NC 6 H 5 

phenyl methyl pyrazolon phenyl dimethyl pyrazolon 

Antipyrine is classed as an artificial alkaloid and like alkaloids 
it unites with acids, hence when prepared in this way it is 
combined with HI. The free antipyrine is separated just as 
strychnine is extracted from strychnine sulphate— by making 
alkaline with NaOH and extracting with ether, from which it is 
crystallized. 

The structural formula for antipyrine is proved by the synthe- 
sis from methyl phenyl hydrazine and aceto-acetic ester. 

(I) CH 3 CH 3 (II) CH 3 

I /CH 3 

C N-NC 6 H 5 

II ,-"ln 



C. iOH HjN-NHC 6 H 5 



CH 



+ 



COOC 2 H. 



CH 



CO (OCAS 



Aceto-acetic ester (enol) 

(III) CH 3 .C=CH 



CH 3 .N 



C = 



NC (1 H, 



PYRAMID ON 



117 



Antipyrine was discovered in a search for artificial quinine. 
It has none of the quinine action on the malarial organism and is 
injurious to the hemoglobin, lessening its oxygen carrying power. 
It is very useful in the treatment of neuralgic pains, and like 
phenacetin is superior to morphine in this condition. It is 
eliminated largely unchanged in the urine though some glycuron- 
ate is formed. 

Pyramidon is said by many to be superior in most respects 
to antipyrine. 

PYRAMIDON 

Pyramidon-dimethylaminoantipyrine is obtained by the fol- 
lowing reactions : a solution of antipyrine hydrochloride is acted 
on by nitrous acid, the result being nitroso antipyrine. 
CH3 CH3 



-N.CH- 



C- 



N.CH; 



CH 



= + HNO ; 



NO-C 



+ H 2 



CO— N.C 6 H 5 CO— N.C 6 H 5 

When this is reduced, amino antipyrine results: 

CH 3 



-N.CH; 



C- 

II 
NH 2 -C 



CO— N.C 6 H 5 

This is isolated by means of its benzylidene derivative, and 
when it is methylated by treatment with methyl iodide it gives 
pyramidon. 

CH 3 



C- 

(CH 3 ) 2 N.C 



-N.CH 3 



CO— N.C 6 H< 



118 CHEMICAL PHAKMACOLOGY 

Pyramidon is a solid, forming in small colorless crystals, 
melting at 108°C. It is easily soluble in alcohol, ether and 
benzene It is soluble in 11 parts of water. A aqueous solu- 
tion saturated at 70°C deposits oily globules of the drug when 
it reaches the boiling point. Its aqueous solution gives a slight 
alkaline reaction. 

Pyramidon is a more powerful base than antipyrine and in 
therapeutics the dose required is only one-third the amount of 
antipyrine that would be given. This drug has been used both 
as an antipyretic and an analgesic, but the latter is the more 
important use. Pyramidon may be prescribed in heart disease 
and nephritis, as it affects the circulation only slightly. It is not 
irritating to the stomach and does not affect the heart, blood, or 
kidneys. It is claimed by some that pyramidon increases 
nitrogenous metabolism, contrary to most antipyrine derivatives, 
and hence should never be prescribed for diabetics. It is useful, 
however, in the chronic fevers of tuberculosis, the acute febrile 
conditions associated with typhoid fever, erysipelas, and pneu- 
monia. In the treatment of all infectious fevers it should be 
used with care, as should all other antipyretics. 

The dosage is usually from 0.3 to 0.4 gm. (5 to 6 grains) 
in tablet form. A single dose is sufficient for twenty-four 
hours. 

Pyramidon is excreted in the urine, partly unchanged, partly 
combined with glycuronic acid and some as uramino-antipyrine, 
a combination of urea and antipyrine: 

CH 3 

C— N.CH 3 

II 
NH 2 .CO.NH— C 

CO— N.C 6 H 5 

Another derivative, rubazonic acid, C20H17N6O2, occurs in the 
urine after standing, and produces a red color due to oxidation. 
lis behavior recalls purpuric acid which is formed when uric acid 
bases and caffeine are oxidized (murexide test). 



TESTS 119 

The tests for pyrarnidon are: 
1. Its melting point 108°C. 

2 Solubility — soluble in 11 parts of cold water, readily soluble 
in alcohol and ether. 

3. Ferric chloride colors the neutral or slightly acidulated 
solution a blue violet color. 

4. Fuming nitric acid colors pyrarnidon solutions blue violet. 

5. Bromine water gives a gray color to pyrarnidon solutions. 

6. Tincture of iodine colors aqueous solutions of pyrarnidon 
blue. 

Acetanilide Tests 

1. It melts at 112°-114°C. It is soluble in 190 parts of water, 
4 of alcohol and 17 of ether. 

2. It gives the phenol isocyanide test as follows: Add 5 cc. 5 
per cent. KOH- and heat. It gives the odor of aniline. Now 
add 1 cc. chloroform and again heat. The odor of the isocyanide 
is produced (see p. 43). 

3. Bromine water gives a white precipitate with an aqueous 
solution of acetanilide. 

4. Heated with a little hydrochloric acid, and an equal volume 
of 5 per cent, phenol added, and then if an equal volume of filtered 
saturated solution of chlorinated lime be added, it acquires a 
brownish red color, which becomes a deep blue on the addition 
of excess of NH 4 OH. 

5. When boiled with KOH as in test 2, aniline is liberated. 
This may be extracted with ether. If, after evaporation of the 
ether, a few drops of calcium or sodium hypochlorite be added 
a violet or purple color changing to dirty red indicates aniline. 



Tests for Antipyrine 

1. Antipyrine is precipitated by the alkaloidal reagents. 

2. Ferric chloride added to 2 cc. of a dilute solution gives a red 
color which changes to yellow on the addition of a few drops of 
sulphuric acid. 

3. To 2 cc. of 1 per cent, antipyrine add 0.1 gram sodium ni- 
trate. The solution remains nearly colorless, but changes to a 



120 CHEMICAL PHARMACOLOGY 

deep green color due to the formation of iso-nitroso antipyrine on 
the addition of 1 cc. dilute sulphuric acid. If the solution be 
concentrated, green crystals of nitroso-antipyrine form. 

4. Fuming nitric acid added to antipyrine gives a green color. 
Heated with excess of nitric acid, it gives a red color. 

5. Add a few drops of sodium or potassium nitrite, then sul- 
phuric acid, a green to blue color appears. If much antipyrine 
be present nitroso antipyrine CnHn(NO)(ON2) will separate 
out in crystals. 

Salicylic Acid Tests 

1. It melts at 156°-159°C. 

2. One gram dissolves in 460 cc. of water, or 42 cc. of chloro- 
form, or 3 cc. of ether. 

3. Its saturated water solution is colored intensely bluish 
violet with ferric chloride solution. 

4. An aqueous solution warmed with Millon's reagent gives a 
deep red color (monohydroxy phenol test). 

5. Bromine water precipitates salicylic acid as tribrom phenyl 
hypobromite - a white crystalline precipitate (see phenol, p. 89) . 

OBr 
y OH 

C 6 H 4 < Mil ! Hr 

^COOH 

Br 



Br 



PHENACETIN: ACETPHENETIDiNE 

1. Acetphenetidine melts at 133°-135°C. 

2. It is soluble in 1310 cc. of water, 15 cc. of alcohol or 90 cc. 
of ether. 

3. Boil several minutes with 3 cc. cone. HC1. Dilute with 
10 cc. water, filter and cool. A few drops of chromic acid or 
chlorine water will produce a green color. 



SACCHARIN 121 

4. Boil with 3 cc. cone. HC1. Dilute to 10 cc, cool and filter, 
and add 2 cc. 5 per cent, phenol, and a little calcium hypochlorite 
solution. A carmine red color develops which changes to blue on 
addition of ammonium hydroxide. 

SACCHARIN 

Saccharin is the ortho sulphonated derivative of benzoic acid, 
and can be prepared from toluene. The following formulas 
indicate the essential reactions: 

/CH 3 
C 6 H 5 CH 3 + H 2 S0 4 = C 6 H/ + PC1 5 = 

X S0 3 H 

y CH 3 
C 6 H/ + NH 3 = 

X S0 2 C1 

,CH 3 ,COOH / C0 \ 

c 6 h/ = c 6 h/ = c 6 h/ )NH + H 2 

X S0 2 NH 2 X S0 2 NH X SO/ 

Benzosulphinidum or 
saccharin 

This substance is not oxidized by the body, and has no food 
value. It is used for its sweetening properties only and for hiding 
disagreeable tastes. It is 300 to 500 times sweeter than cane 
sugar, and has been used in the past as an adulterant of food 
products. 

It is a white, crystalline powder, acid in reaction with a faint 
aromatic odor. One grain dissolves in 290 cc. water or 31 cc. 
alcohol, or about 25 cc. boiling water. It is very soluble in 
chloroform or ether. It dissolves readily in alkalies. It liberates 
C0 2 from carbonates which forms a salt by replacement of the 
imide hydrogen (compare with phenol). 

0.2 Gram in 10 cc. of sulphuric acid, when kept at 48°-50°C. 
for 10 minutes, gives not more than a trace of color. It will not 
reduce Fehling's solution. With ferric chloride it gives no phe- 
nolic reaction, or precipitate — absence of phenols and benzoic acid. 
It is excreted in the urine unchanged. 



122 



CHEMICAL PHARMACOLOGY 
THYMOL IODIDE 



Thymol iodide, or aristol, is a compound obtained by the con- 
densation of two molecules of thymol and the introduction of two 
atoms of iodine into the phenolic groups: 



10 



CH; 



CH : 



CH; 






01 



CH; 



! 

c 
/\ 

CH3 CH; 



This is a reddish yellow bulky powder containing 45 per 
cent, of its weight of iodine. It has a slight aromatic odor, 
and has been used to replace iodoform as a dusting powder, 
but is much inferior to it as an antiseptic. It is insoluble both 
in water and glycerol, and is slightly soluble in alcohol, but 
is soluble in ether, chloroform, or collodion. The antiseptic 
action of all these iodine-containing organic compounds is due 
to the liberation of free iodine. The pure product contains 
no free iodine since it does not color starch paste. The 
amount of iodine in the product and the amount of thymol 
iodide can be determined therefore by determining the iodine 
content as follows: 

Dry over sulphuric acid in a desiccator. 

Mix 0.25 gram with 0.3 gram anhydrous sodium carbonate 
in a crucible. Cover the mixture with another gram of anhy- 
drous sodium carbonate. Gradually raise the temperature to 
that of dull redness, and hold at this temperature until the whole 
is carbonized completely. This converts the iodide into sodium 
iodide. Cool and extract with hot distilled water. Filter and 
wash until the filtrate shows no test with silver nitrate (all the 



PHENOLPHTHALEIN 123 

iodide has been dissolved) . Evaporate the filtrate and washings 
to 150 cc. on a water bath, and add an aqueous solution of 
KMn0 4 (1 : 20) until the hot liquid remains permanently pink. 
This converts the I into KI0 3 . Add enough alcohol slowly to 
remove the pink color which is a disturbing factor, make to 200 
cc. Mix well, filter through a dry filter, reject the first 50 cc. 
and take the next 100 cc. = H the whole, for determination. 
Add 1 gram of pure KI and acidify distinctly with H 2 S0 4 . 
Titrate the liberated iodine with tenth-normal sodium thiosul- 
phate, adding starch solution near the end, as an indicator. 
Each cc. of tenth-normal sodium thiosulphate corresponds to 
0.002115 gm. of thymol I. In the reaction the acid added 
converts the KI0 3 into the bi-iodate KH(I0 3 )2 and this liberates 
iodine from the added potassium iodide according to the formula : 

KH(I0 3 ) 2 + 10KI + 11HC1 = 121 + 11KC1 + 6H 2 
12 )389.94 12 )1523 .04 

10 )32.495 10 )126.92 

3.2495 gm. 12.692 gm. in 1000 mils ^ V.S. 



Since in this reaction 12 atoms of iodine are titrated but 
only 2 atoms of this or J£ comes from the thymol, the I. factor 
for the thymol is Y§ of 12.692 or in tenth-normal solution % of 
0.012692 = 0.002116 gm. iodine per cc. thiosulphate. 

PHENOLPHTHALEIN 

This phenol derivative has always been important in chemistry 
as an indicator. It has recently been used in medicine as a mild 
cathartic either by itself or mixed with other substances, as agar. 
Kidney function ha's been determined by its use, but for this 
purpose its derivative phenolsulphonephthalein is more com- 
monly used. 

Formation of phenolphthalein: 

When toluene is treated with bromine at ordinary tempera- 
tures in the absence of direct sunlight, bromine may be 
substituted for H in the ring, a mixture of ortho, meta and para 
brom toluene being obtained: 



124 



CHEMICAL PHARMACOLOGY 

CH.3 CH3 CH; 

Br 



Br 



ortho 



meta 



Br 

para 



If ortho brom toluene is treated with methyl bromide and 
sodium, xylene is formed: 



CH, 



Br 



+ CH 3 Br + 2Na = 



CH, 



CH : 



+ 2NaBr 



O. xylene on oxidation gives phthalic acid: 



CH. 



CH 3 



+ 40 = 



COOH 



+ 2H 2 



COOH 



Phthalic acid 
When phthalic acid loses water, phthalic anhydride results: 



C();OH 
COOIH 



CO 



CO 



/ 







This combines with two molecules of phenol to form phenol- 
phthalein: 



PHENOLSULPHONEPHTHALEIN 



125 



CIO 


H 


>0 
C-0 




H 



OH 



OH 



or 



,C 



/ 



C 6 H 4 OH 



C 6 H 4 OH 



CcH/ 

\l 

x CO 



While phenolphthalein is insoluble in water it is dissolved by 
the bile in the intestine and develops a mild irritant action. It 
is used in medicine almost solely for its cathartic effect. In this 
respect it resembles the senna group of cathartics, but has the 
advantage of being tasteless, and can be made readily into tablets. 

yC6H<K 



Nosophen,(C 6 H 2 I 2 OH) 2 C 



CO, or tetraiodophenol- 



phthalein, is a powerful antiseptic. It is an iodine compound in 
which the iodine is attached directly to the ring; consequently, 
it is but little if any broken down by the body. When taken 
internally it is not absorbed but passes through the system un- 
changed, a small amount being absorbed and excreted by the 
kidneys unchanged. If the urine is alkaline it has a pink color. 
This absorption and excretion may be shown by taking 0.15 gram 
phenolphthalein in a capsule, collecting the urine every hour for 
three hours and making it alkaline with sodium hydroxide. It 
has been used as a dusting powder. Since it contains two 
hydroxyl groups, it can form salts with the heavy metals such 
as bismuth, iron, mercury, and zinc. 



126 CHEMICAL PHAKMACOLOGY 

Phenolsulphonephthalein : 

Ce-KU C6H4OH 

so 2 c 

O C 6 H 4 OH 

is a product of the interaction of phenol and sulphobenzoic acid 
anhydride : 

C 6 H 4 

/\ 
S0 2 COo 



o 

This phthalein is a bright red crystalline powder slightly 
soluble in water and alcohol with a yellow color, but soluble in 
dilute alkalies, in which it gives a purer red than phenolphthalein. 
It is used in medicine to test the kidney function. When 6 
mgm. are injected intramuscularly or intravenously, 60-80 per 
cent, of it is excreted by the normal kidneys within two hours. 
The amount excreted is determined by making the urine alkaline 
and comparing the color with a known concentration of the drug 
treated in the same way. 

Determination of Kidney Function 

Give the patient about 300 cc. water to insure diuresis. In 
twenty minutes the bladder should be emptied, and 6 milligrams 
of the phthalein injected into a large muscle. The phthalein for 
injection can be procured on the market in solution ready for use. 
The time of injection is noted, and the urine collected at the end 
of one hour and ten minutes and again one hour after the first 
collection. Keep the samples separate, and determine the amount 
of phthalein excreted immediately or, if this cannot be done, 
preserve by the addition of phosphoric acid until the determina- 
tion can be made as follows: 

Make both samples sufficiently alkaline with 20 per cent. NaOH 
to bring out the maximal color. Dilute to 1000 cc. with water 



NAPHTHALENES 



127 



and filter. Compare the color with that produced by 6 milli- 
grams of the phthalein in a liter of water or normal urine treated 
in the same way. A colorimeter may be used, but sufficiently 
accurate results may be obtained by diluting the standard in a 
graduated cylinder until the colors are matched. 

In normal cases 40 to 60 per cent, of the drug should be 
eliminated in the first hour and 20 to 25 per cent, more in the 
second hour, making a total of 60 to 85 per cent. 

XIV. NAPHTHALENES (Tar Camphor) 

Naphthalene occurs in coal tar in larger quantities than any 
other hydrocarbon and it is rather easily isolated. It is also 
formed when the vapors of many organic compounds are passed 
through red hot tubes. The luminosity of coal gas is largely 
dependent on its naphthalene content. Distillation takes place 
between 170° and 230°. The pure product melts at 79° and 
boils at 218°. It crystallizes in large lustrous plates and has a 
characteristic odor. Clothing may be protected from moths by 
naphthalene which is used in the form of moth balls. On 
oxidation, naphthalene and its derivatives may yield phthalic 
acid (p. 124), which is used in the preparation phenolphthalein. 



+ 90 



COOH 



COOH 



Naphthalene 



N0 2 

Phthalic acid Nitronapthalene 



+ 90 



COOH 



COOH 




+ 90 



COOH 
COOH 



N0 2 NH 2 

Nitrophthalic acid Amino napthalene Phthalic acid 



128 



CHEMICAL PHARMACOLOGY 



Napthalene compounds, while extensively used in the manu- 
facture of dyes, are but little used in medicine; some are 
employed principally as antiseptics and preservatives. 

The products most used are the a and (3 napthols: 



napthol 



napthol 



OH 



OH 



These give the reactions of the phenols. The a napthol is far 
more toxic than the /? napthol, and is not employed in medicine. 
/3 napthol is used mainly in dermatology, and as an intestinal 
antiseptic. It has been used in the treatment of hookworm, 
and as a food preservative. Its use as a hookworm remedy is 
much less important since thymol and oil of chenopodium have 
been used. 

Beta-napthol combines with benzoic acid to form benzonapthol 
and with salicylic acid to form 8 napthol salicylate. Betol 
is a proprietary (3 napthol salicylate. 

The napthols are eliminated from the body, combined with 
glycuronic and sulphuric acids. Most phenols are excreted in 
this way. 

ANTHRACENES 



The anthracenes are a very important group of drugs. Many 
of the most used cathartics owe their action to anthracene 
derivatives. 

Anthracene is a derivative of coal tar, and can also be prepared 
synthetically. The dye alizarin, or " Turkey red," is prepared 
from it. Crystallization is in colorless plates which melt at 213° 
and boil at 351°C. 

Its synthesis from ortho brom benzyl bromide and sodium is 
shown by the reaction : 



ANTHEAQUINONE 



129 



Br BrCIL 



CH 2 Br Br 

4.Na 




+ 4NaBr+2H 



Anthracene may also be prepared by the method of Anschut; 
from benzene, aluminum chloride, and tetrabrom ethane. 



BrCH.Br 
CeHe + + CeH 

BrCH.Br 



/ CH \ 

CcH 4 v yCoH. 

Anthracene 



This synthesis proves the structure of anthracene to be two 
benzene nuclei, united by the groups CH — CH linked to the 2 
ortho atoms of the benzene nuclei. 

Nitric acid converts anthracene into anthraquinone. 




Anthraquinone 

The active principles of senna, rhubarb, cascara, aloes, etc., 
consist of the anthracene derivatives, emodin, cathartin, chrys- 
ophanic acid, and their compounds. 



130 



CHEMICAL PHARMACOLOGY 





Emodin or trioxymethyl anthra- 
quinone 




Chrysophanic acid or dioxymethyl 
anthraquinone 
These substances occur in the glucosides of rhubarb. The 
digitalis glucosides also are anthracene derivatives. 

QUINONES 

The quinones are a peculiar class of substances that have no 
analogues in the aliphatic series. Benzo quinone was the first 
number, and was prepared from quinic acid. There is some 
doubt about the formula — two forms being given: 
O 



i. 



and 



O 



O 



O 

Formula No. 1 is most generally accepted. The accepted 
formula agrees with the fact that quinone readily adds four 



QUTNONES 



131 



bromine atoms, and behaves like a diketone and unites with two 
molecules of hydroxylamine with a loss of two molecules of water 
to form quinone dioxime: 

N— OH 



0+2 NH 2 OH 




+ 2 H 2 



N— OH 



O 

Quinone in the body is reduced to hydroquinone (quinol) which 
in turn unites with sulphuric and to some extent glycuronic acid. 
Vieth (quoted by May) has investigated the purgative action 
of the synthetic anthra quinones, and his results indicate that the 
position of the OH groups has some relation to the activity, and 
that the presence of the methyl group has little influence. The 
structure of the molecule is indicated as follows: 




The purgative action of the products arranged in terms of the 
strongest, or anthrapurpurin as 1 is shown in the following table : 

This purgative action also gives some indication of the length 
of time the substance remains in the intestine — chrysophanic 
acid because of its rapid absorption exerts little cathartic action. 



132 



CHEMICAL PHARMACOLOGY 



Substance 



Strength 
of action 



Anthrapurpurin 


1-2-7 trihydroxy-anthraquinone 


1 


Flavopurpurin 


1-2-6 trihydroxy-anthraquinone 


K 


Anthragallol 


1-2-3 trihydroxjr-anthraquinone 


H 


Purpuroxanthin 


1-3 dihydroxy-anthraquinone 


H 


Alizarine-Bordeaux 


1-2-3-4 tetrahydroxy-anthraquinone 


Ho 


Purpurin 


1-2-4 trihydroxy-anthraquinone 


Mo 







Anthra purpurin diacetate has been sold as a purgative, but it 
is absorbed to a considerable degree and irritates the kidney. 
Anthraquinone acts more like a diketone than a true quinone. 
It is readily reduced in the body, and readily forms an oxime 
with hydroxylamine (see quinone). Emodin is partly absorbed 
and is then excreted in the urine, which turns red on the addition 
of an alkali. Sufficient may be excreted in the milk to purge an 
infant. In passing through the intestine all these drugs may 
produce griping, and since they do not cause evacuation until 
they enter the large intestine they are thought to act only on this 
part of the tract. 

An important derivative of anthracene is acridine: 

N 



and phenyl acridine: 




HETERO CYCLIC COMPOUNDS 



133 



These are the basis of a few technically important dye stuffs, 
which are amino derivatives of these compounds. These acridine 
dyes are among the list of industrial poisons to which the atten- 
tion of physicians practicing in industrial communities has been 
called by the Bureau of Labor in Bulletin, May, 1920. 

XV. HETERO CYCLIC COMPOUNDS 

This is a group of nitrogen bases which are of interest chiefly 
as being the important nuclei of akaloids. These are pyridine, 
quinoline, isoquinoline, and related bodies. They are found to 
some extent in the light oil of coal tar, in which they are the basic 
constituents. 

Pyridine has the formula. 




It may be regarded as an ammonia derivative in which the 
valences of the nitrogen are occupied by a ring. The alkaloids 
have a similar structure. The nitrogen of pyridine, being un- 
saturated, can add acids as does ammonia, e.g. : . 



N 



H CI Pyridine hydrochloride. 

Pyridine can be obtained from coal tar, bone oil, and can be 
prepared from penta methylene diamine by heating : 



134 CHEMICAL PHARMACOLOGY 

/CH 2 — CH 2 — NH H 



CH/ + ! H 

X CH 2 — CH 2 — ;NH 2 




+ NH ; 



NH 

Piperidine 

+ 3H 2 



N 
Piperidine + 3. oxygen-* Pyridine + water 

There are other ways of preparing pyridine, as by the condensa- 
tion of aceto-acetic ether as described under antipyrine formation. 



XVI. CARBOHYDRATES 

The greatest part of plants consists of compounds of carbon, 
hydrogen, and oxygen, called carbohydrates. In most of these 
compounds the hydrogen and oxygen are in the same proportion 
as in water. They are classified as follows : 

1. Monosaccharides, the glucose group, or monoses, simple 
sugars, including glucose, fructose, galactose, pentose, etc. 
These will not yield simpler sugars on hydrolysis, but break into 
smaller molecules. Water and C0 2 are the ultimate products, 
whether oxidation occurs in the body or in the test tube. 

2. Disaccharides, the cane sugar group (bioses, saccharbioses) , 
include cane sugar, maltose, lactose, etc. On hydrolysis 
these break up into simpler sugars, or monosaccharides. The 
hydrolytic products are the same in the body as in the test tube. 

3. Polysaccharides, the cellulose group (or amyloses amyloids), 
which include starches, glycogens, gums, pectins, celluloses, etc. 
They are not sugars, but can be hydrolyzcd into sugars. 



CARBOHYDRATES 135 

The carbohydrates are of importance primarily as food ; and 
secondarily as medicines. 

The main carbohydrates used in medicine are: acacia, traga- 
canth, starch, flaxseed, cane sugar, fructose, and glucose. 

DIFFERENCE BETWEEN STARCHES, GUMS, CELLULOSES AND 

SUGARS 

1. The products of digestion are different. Starch breaks down 
during digestion as follows : 



Starch (C 6 H 


ioOjs)x 


/\^ 




Maltose 


^Amylodextrin 




/\ 




/ \ 




/ \ 


Maltose Erythrodextrin 




x\ 




/ \ 




/ \ 




Maltose Achrodextrin 




/\ 




/ \ 




./ \ 




Maltose Maltose 



" / \ 

Glucose Glucose 



C0 2 H 2 C0 2 H 2 

There are probably many intermediate products between these 
such as other dextrins, alcohol, etc., and probably other sugars 
formed, but the final products are, in all cases, carbon dioxide 
and water. Often some sugars and dextrins are found in cooking 
and this is why cooked food is sweeter than uncooked. 

General Tests 

1. Examine the various gums, sugars, and celluloses, and make 
notes of the physical differences. 



136 



CHEMICAL PHARMACOLOGY 



2. Test the solubility in water and alcohol (see under 
mucilages). 

3. Molisch's Reaction. — Treat the carbohydrate in solution 
with a few drops of 15 per cent, alcoholic solution of alpha 
napthol. Then add slowly, sliding down the side of the tube, 
enough H 2 S0 4 to form a layer at the bottom of the tube. A 
reddish violet band appears at the line of contact. This reaction 
reveals the presence of a carbohydrate even when in combination 
with protein. The test is due to the formation of furfurol 
(furfural or f urfurane aldehyde) . 



It has the formula C 4 H 3 O.COH 




HCO 



On oxidation it yields pyromucic acid = 




COOH 



Mucic acid (q.v.) also yields pyromucic acid on destructive dis- 
tillation. Furfural results from the oxidation of pentoses and 
pentosanes (sawdust, gums, bran, etc.) The name comes from 
furfur = bran. It is contained in beer, brandy, fusel oil, etc., 
and was formerly thought to modify the intoxication by fusel 
oil, but it is not so considered now. It is a colorless oil, has a 
pleasant odor and gives the aldehyde reactions. 

(a) To show the presence of furfural : Place about 3 grams of 
bran, gum arabic, or any of the above mentioned substances in a 
distilling flask. Add 100 cc. 12 per cent. HC1. Distil over 
10-30 cc. Let it drop on a filter paper moistened with aniline 
acetate or a mixture of 5 drops colorless aniline and 8 drops 
of acetic acid. Note the color; add a few drops of this to a few cc. 
of the distillate. 

(b) Treat the distillate with a few drops of 15 per cent, alco- 
holic solution of a napthol. Compare with Molisch's test. 



CARBOHYDRATES 137 

STARCHES (C 6 H 10 O 3 )x 

Starches yield maltose and hexose sugars only on hydrolysis. 
The vegetable gums and mucilages in addition to hexoses give an 
abundance of pentoses. 

Galactose is often found among the gum hexoses, consequently 
when oxidized with nitric acid gums yield mucic acid (COOH 
(CHOH) 4 COOH). 

Starches, dextrins, dextose, levulose, cane sugar, or maltose 
do not yield mucic acid on oxidation. 

Tests for Starch 

1. Add a few drops of iodine solution to a little thin starch 
paste. The resultant blue color is due to C 6 Hi O 5 I. When 
heated, the color disappears, to reappear on cooling. The color 
can be destroyed bj T adding anything that has a stronger affinity 
for the (I) than has starch, e.g., Ag salts, alkaline hydrates, and 
sodium thiosulphate (see decolorized tincture of iodine). 

2. Test starch solution with Fehling's solution. No reduction. 

3. Boil a solution of starch with a few drops of dilute H 2 S0 4 . 
Neutralize, or make slightly alkaline with KOH or NaOH, 
and again try Fehling's test. This time there is a reduction. 
Explain. 

Note. — Fehling's solution is reduced by anything containing 
aldehyde or ketone groups. The reducing sugars are either aldo- 
ses or ketoses. The statement is sometimes made that the reduc- 
tion is due to the aldehyde and ketone groups, and in the case of 
these simple sugars this may be correct, but the fact that chloro- 
form, adrenalin and other drugs reduce Fehling's solution renders 
the explanation questionable. Fehling's solution on standing 
also reduces itself because of the tartrate it contains, and tartrates 
contain no aldehyde or ketone groups. A. P. Mathews thinks 
that the alkali of the Fehling breaks the sugar into fragments 
and these fragments are reducing bodies. 

4. Dry starch treated with I in KI solution gives a brown 
color. 

5. Starch paste when hydrolyzed by saliva or acids fails to 
give the iodine reaction. 



OH 




OHO H 


1 / 




1 1! 1 


o-c 


or 


— c— c— c- 



138 CHEMICAL PHARMACOLOGY 

SUGARS 

Sugars are predigested foods. The bioses are hydrolyzed into 
monoses before absorption. The characteristic sugar group is an 
aldehyde or ketone group with one or more 



H 



H H H H H 

hydroxyl groups. Invariably one hydroxyl group is in the alpha 
position with reference to the aldehyde or ketone group. 

Tests for Sugars 

1. All sugars give Molisch's reaction. This is a general test 
for carbohydrates. See p. 136. 

2. With iodine, starches give a blue color; gums, a port wine 
color; sugars, no reaction, and celluloses, no reaction. 

3. With Fehling's solution, starches, gums, and celluloses give 
no reduction until they are hydrolyzed. Cane sugar does not 
reduce it until inverted, while all other common sugars reduce 
Fehling's solution directly. 

Apply Fehling's test to a solution of cane sugar. Hydrolyze 
as under acacia, and again test. Explain and write reaction. 

4. Fermentation. — -Pentoses do not ferment with yeast as all 
other common simple sugars do. Maltose ferments directly, cane 
sugar and lactose only after hydrolysis. To a 2 per cent, solution 
of each of these sugars add a small particle of yeast and keep at a 
temperature of 40°C. Results? 

The Uses of Sugars. — They are used as flavoring and sweeten- 
ing agents in medicines, and in strong solutions as preservatives. 
Molasses is used in domestic medicine as a laxative. Lactose is 
used in the preparation of infant foods and as an excipient or 
vehicle in pharmacy. Levulose is sometimes given to diabetics 
who cannot utilize glucose, but the advisability of this is question- 
able since it is perhaps as difficult to oxidize in the body as 
dextrose and other sugars. In cases of glycosuria it is often neces- 
sary to distinguish between pentosuria, levulosuria, lactosuriaand 
glucosuria. % To determine this, differences of rotation, fermenta- 



CARBOHYDRATES 139 

tion, the melting point of the osazone and other tests must be 
made. 

CELLULOSE 

Cellulose is a mixture of complex carbohydrates. Next to 
water, it is the most abundant substance in plants where it consti- 
tutes the greater part of the cell wall. Because it is not a pure 
chemical, it is often called crude fiber. Celluloses are not diges- 
tible except by strong reagents and the higher animals digest 
but little cellulose, although some of the lower animals do. 
This in digestibility renders cellulose valuable in the treatment of 
chronic constipation. In such cases cellulose acts by stimulating 
the bowel mechanically. Apparently some indigestible volume 
is needed to elicit the normal function of the intestine. This is 
one of the reasons why fruits and vegetables are so highly 
recommended in cases of chronic constipation. 

The celluloses include vegetable fibers, cotton, linen, hemp, 
filter paper, etc. They are insoluble in water, alcohol and ether. 
While they are indigestible, strong H 2 S0 4 converts them into 
dextrin and glucose. Treated with HN0 3 , cellulose yields gun- 
cotton, cellulose hexanitrate, which is highly explosive. If the 
HN0 3 is allowed to act a short time only, the tetra and penta 
nitrates are formed. These are not explosive, and dissolve 
readily in a mixture of alcohol and ether with the formation of 
collodion (see collodion and flexible collodion.) 

Tests for Cellulose 

1. Examine guncotton. Test its solubility in water and 
alcohol. 

2. Dip a piece of filter paper in a mixture of 4 volumes of 
H 2 S0 4 and one of water and immediately wash it off with water. 
Let dry and apply the iodine test. Compare the test with the 
original paper. 

3. Crude Fiber. — The term fiber is applied to those carbo- 
hydrate products in drugs or in food which are insoluble in 
dilute acids and alkalies. Inasmuch as they are not pure cellu- 
lose, they are often designated as crude fiber. 

To determine the amount of crude fiber in a food or drug: 
Weigh out 2 grams of the dry material. Extract with ether until 



140 CHEMICAL PHARMACOLOGY 

all lipoids are extracted. Boil the residue with 200 cc. of 1.25 
per cent. H 2 S0 4 for 30 minutes, using a reflux condenser. 
Filter through asbestos, wash with boiling water. Transfer the 
asbestos, etc., to the flask again and repeat boiling with 1.25 per 
cent. NaOH 200 cc. Boil for 30 minutes, filter through a Gooch 
crucible and wash free from alkali with hot water. Dry at 
110°C. until the weight is constant. Incinerate and weigh 
again. The loss in weight is considered to be crude fiber. 

HEMICELLULOSE 

Hemi, pseudo, reserve cellulose, or paragalactane substances 
are not well defined and seem to be mixtures of mannans, xylans, 
arabans, galactans, or complexes which when treated with hot 
dilute HC1 or H 2 S0 4 may yield galactose, rhaminose, mannose, 
fructose, arabinose, or xylose, whereas ordinary cellulose does 
not, except when treated with strong acids. The seeds of many 
plants, especially nut shells and stony seeds, cocoanut rind, and 
young plant tissues, contain the reserve carbohydrate which is 
called hemicellulose. It serves as reserve food or supporting 
tissue. From its reactions hemicellulose is considered simpler 
than cellulose in composition. When boiled with acid the only 
product of hydrolysis is a hexose. Hemicellulose is also dissolved 
by dilute alkali and by means of enzymes, and may be converted 
into gums. The formation of galactose on hydrolysis suggests 
a relationship to the gums. 

AGAR 

Agar (agar-agar) is a carbohydrate extracted with hot water 
from certain marine algae which grow mainly along the eastern 
coast of Asia and Japan. The extract is evaporated and the 
product sold in bundles of shreds, or as a powder. It consists 
practically of the hemicellulose, gelose, (C 6 Hio0 5 ), and dissolves 
in 500 parts of water. When boiled with about 500 parts of 
water for 10 minutes, it yields a stiff jelly on cooling. It is used 
principally in the preparation of bacterial culture media, and 
because of its indigestibility has been recommended asacathartic. 
In this respect it acts like bran and vegetables rich in cellulose. 
Phenolphthalein agar, is agar impregnated with 3 per cent, phenol- 



CARBOHYDRATES 141 

phthalein to increase its laxative effect. Regulin is another 
preparation of agar with cascara. 

Agar, because of its cheapness and good jelling properties, has 
been employed as a "coagulator" in the manufacture of cheap 
jellies. To detect agar in such jellies the product is heated with 
5 per cent, sulphuric acid, a little permanganate is added, and 
after the material settles, diatoms in large numbers will be found 
if agar has been used. 

GUMS 

Gums are desiccated exudations of certain plants, obtained by 
incising the limbs or branches. They are somewhat transparent 
carbohydrates, isomeric with starch. Acacia and tragacanth are 
the most important. They have a physical action only and are 
used mainly as excipients or vehicles (see mucilages and demul- 
cents). Their use is objectionable in cases where they are hydro- 
lyzed by bacteria and the products remain as irritating 
substances. They are but little used externally for this reason. 
Pectin or vegetable jelly is closely related to the gums and causes 
fruit to set or "gel". Gums lessen the irritation of medicines 
and are used in enemata where it is desirable to retain the solution 
in the rectum for some time. The taste of acids or salts is also 
lessened bjr being mixed with colloids, as in fruits. Raspberries 
contain more acid than currants but taste less acid because they 
contain colloid. These effects are due to lessened absorption 
and also to protection of the sensory nerve endings by the 
colloidal material. 

Tests for Gums 

1. Test the solubility of gum acacia and tragacanth in water 
and alcohol. 

2. Mix watery solution of acacia with an equal volume of 
alcohol. Result? What has happened? Compare with glu- 
cosides under the same treatment. What is the difference? 

3. Test a water solution of acacia or tragacanth with Fehling's 
solution. 

4. Test a water solution of a gum with iodine solution. 
Compare results with starch solution. Note differences. 

5. To a solution of acacia in a test tube add a few drops of 



142 CHEMICAL PHARMACOLOGY 

H 2 S0 4 . Boil for two or three minutes. Neutralize with KOH 
or NaOH and test with Fehling's solution. 

6. Compare the taste of a 1 per cent, citric acid in water with 
1 per cent, citric acid in 10 per cent, mucilage of acacia. 
Explain. 

7. Mix a small quantity of cottonseed oil with 3 volumes 
mucilage of acacia and shake until an emulsion is formed. Add 
alcohol to the mixture and note results. Explain. 

8. State the differences between starches, sugars, and gums; 
between gums and glucosides; glucosides and alkaloids. 

PECTINS 

Pectins are carbohydrate bodies whose composition is known 
but slightly. They are associated with cellulose in the plant. 
It is due to pectin that fruit juices "gel". The phenomenon of 
gelling is similar to the setting of gelatin, but the composition of 
the gelling body is different in the two cases. In the case of 
gelatin it is a protein, while pectin is a carbohydrate. 

Pectin is especially abundant in apples, pears, gooseberries 
and currants. It is also found in abundance in carrots, beet 
roots, etc., as pectose, which as ripening proceeds is converted 
into pectin. 

The clotting of plant juices is said to be due to an enzyme 
pectase, but that it will occur without enzyme action is apparent 
from the gelation after prolonged cooking which destroy enzymes. 
According to Duclaux and others the clotting of pectin is due to 
the presence of calcium salts and the presence of an enzyme is 
unnecessary. The clotting therefore would seem similar in 
nature to the clotting of blood. According to Freimy (Jour. 
Pharm. et chim., 1840, 26, 368) the hardness of unripe fruit is 
due to pectose. When this is boiled with dilute acids or alkalies, 
pectin, parapectin, metapectin, and pectic acid are formed. 
Some of these exist in the plant combined with calcium, in the same 
sort of union as that which occurs in gums. 

No very characteristic tests for pectins can be given. Methyl- 
ene blue and some other substances stain pectins but not pure 
cellulose, while crocein, napthol black and orseille, stain cellulose, 
but not pectin. Pharmacologically pectins may exert a vitamin 
effect, but this is not proven. 



FATS AND OILS 143 

METHOD OF PREPARING PECTIN 

(C. H. Hunt, Science, 48, 201, 1918) 

The object in view was to prepare pectin, so that it could be 
added to fruit juices which are low in pectin, and so cause a 
gelling of non-gelatinating juices: The method was as follows: 

Dried apple pomace (60 g.) was boiled with 3 successive 
portions (200 cc. each) of H 2 0, and filtered after each boiling. 
For each 100 cc. of filtrate, 25 g. (NH 4 ) 2 S0 4 were added; the re- 
sulting solution was heated to 70°; the pectin separated as a 
grayish white flocculent precipitate which was collected on a 
filter, dissolved in hot H 2 0, again precipitated with (NH 4 ) 2 S0 4 
and collected on a filter, dried at 60 to 70°, then washed several 
times with cold H 2 to remove adhering (NH 4 ) 2 S0 4 , and again 
dried. The product was tested for gelatinizing power "by adding 
to a 1 per cent, solution of the pectin 0.5 per cent, solution of 
citric acid and 65 g. of sugar. This solution was boiled for 10 to 
20 minutes and upon cooling a nice stiff jelly was produced. 
The taste did not indicate the presence of (NH 4 ) 2 S0 4 and upon 
dissolving the jelly in hot H 2 only a slight milkiness was pro- 
duced when tested for sulphates." If wet pomace be used, in 
addition to the 25 g. (NH 4 ) 2 S0 4 per 100 cc. of filtered extract, 
that salt must be added in extra portions 5 g. each until precipita- 
tion of the pectin occurs; it may also be precipitated by saturation 
of the filtered extract in the cold (NH 4 ) 2 S0 4 . The (NH 4 ) 2 S0 4 
method gave a yield of 6.33 per cent, pectin, the alcohol method a 
yield of 6.91 per cent. Concentration of the pectin extract either 
at a temperature below the boiling point or by freezing did not 
impair the' quality of the pectin and reduced the amount of (NH 4 ) 2 
S0 4 required. 

XVII. FATS AND FIXED OILS 

Fats and fixed oils are salts of glycerine with fatty acids, the 
acids being principally palmitic, stearic, and oleic, or mixtures 
of these. The oils are liquid fats. The consistency of fat 
depends upon the relative amount of the acids present: if 
stearic acid only is present, the fat is hard (e.g., oil of theobroma- 
cocoa butter) ; if oleic acid is the principle one present, the fat is 
soft or oily (as in all the ordinary fixed oils). Tallow is the fat 
from beef and mutton suet, while lard is hog fat. To obtain these 



144 



CHEMICAL PHARMACOLOGY 



relatively pure, the fats are sometimes kneaded in a muslin bag 
under hot water. The pure fat separates and floats on the sur- 
face, while the connective tissue is held in the bag. High heat 
decomposes fats with a resultant formation of irritating sub- 
stances (acrolein — acrid oil). Vegetable oils are obtained by 
expression of the seeds, which, when the fats are solid, are often 
heated to liquefy the oil and facilitate the process. The fixed 
oils are entirely different from the volatile oils (q.v.). 

Fats are sometimes called glycerides, glycerine esters, or etheral 
salts. Glycerine with stearic acid alone is called stearin, or 
glyceryl stearate; with palmitic acid, palmitin, and with oleic 
acid, olein. The combination is represented by the following 
formulas — where R represents any fatty acid radical: 



CH 2 0!H HOjOC.R 

I ::::::: 

CHOlH HO OCR 



CH 2 O.OCR 



CH.O.OCR + 3H 2 



CH 2 OiH HOjOC.R 

Glycerine + fatty acid 
Stearic acid 
Stearin 
Palmitic acid 
Palmitin 
Oleic acid 
Olein 



CH 2 O.OCR 

Fat + water 
C17H35COOH 

C3H5(Ci8H350 2 )3 

C 15 H 31 COOH 

C3H5(Ci6H 3 i0 2 )3 

C 17 H 33 COOH 

C 3 H 5 (C 1 8H3302)3 



CLASSIFICATION OF OILS 

Oils are divided into drying and non-drying. Some oils which 
contain linolenic and linolic acids when exposed to the air absorb 
oxygen and become resinous and leave a hard elastic film. This 
process is hastened by catalytic agents such as litharge, manga- 
nese dioxide and the acetates and borates of lead, manganese, and 
zinc. These agents are known as " driers." Oleic acid does not 
absorb oxygen. The drying oils are less viscous and less stable 
than the non-drying. This drying and unstable property is due 
to the unsaturated fatty acids. The drying vegetable oils are: 



FATS AND OILS 145 

I. The linseed oil group which includes: 

Linseed 

Hempseed 

Walnut 

Sunflower 

Poppyseed 

Nigerseed 

The semi-drying or cottonseed oil group includes: 

Cottonseed 

Sesame 

Beechnut 

Maize 

Rape 

Brazil nut 

This group is composed mainly of the glycerides of oleic and 
linolic acids. 

II. The non-drying or castor oil group includes: 

Castor 
Croton 

The non-drying olive oil group includes : 

Olive 
Almond 
Rape 
Peanut 
Mustard oils 

Most animal fats and waxes are non-drying, but the fats of the 
rattlesnake and ice bear are drying, while horse fat is semi-drying. 

Both animal and vegetable fats and oils are used in medicine. 
The most important animal fats are lard or swine fat, suet or 
mutton fat, tallow or beef fat, and butter fat. 

The relative amount of the various fatty acids in these differ- 
ent fats varies widely, not only with the species but also with the 
food of the animal. Lard may contain 90 per cent, olein and 
melt as low as 28°C. when the diet is corn-meal, or as high as 35°C. 
when the animal is fed on oats, peas and barley; the fat in this 
case contains less olein than when the. animal is corn fed. Fat 
10 



146 CHEMICAL PHARMACOLOGY 

from different parts of the same animal may vary in melting 
point due to differences in composition. Human fat melts as 
low as 17.5°C. because it is rich in olein, tallow melts at about 
45°C, and suet at 45-50°C. If a fat contains only oleic acid 
with glycerine it is an olein or triolein and is a liquid at 0°C, 
while palmitin (tripalmitin) melts at 62°C. and stearin (tri-stearin) 
at 71.5°C. 

Butter fat is a mixture of palmitin, stearin and olein, and in ad- 
dition it contains 6 to 8 per cent, of volatile fatty acids combined 
with glycerine. These are butyric, caproic, capryllic, capric, 
with traces of lauric and myristic. No other fat except cocoa- 
nut oil contains so high a percentage of volatile fatty acids. 
This fact aids in the recognition of an adulteration of butter with 
other fats as in oleomargarine, which consists chiefly of the higher 
fatty acids. Butter is little if at all used as a medicine, but it is 
extremely valuable as a food and contains vitamines essential to 
normal growth, which few if any other fats can adequately 
supply. 

Fats and oils are widely distributed in the vegetable kingdom, 
chiefly as the glycerides of palmitic, stearic and oleic acids, but 
the following fatty acids are frequently found : 



I. Isobutyl acetic or 


CH 

caproic 

CH 


^)CH.CH 2 .CH 2 .COOH 

3 


Caprylic 






CH 3 (CH 2 ) 6 COOH 


Capric 






CH 3 (CH 2 ) 8 COOH 


Lauric 






CH 3 (CH 2 ) 10 COOH 


Myristic 






CH 3 (CH 2 ) 12 COOH 


Palmitic 






CH 3 (CH 2 ) 14 COOH 


Stearic 






CH 3 (CH 2 ) 16 COOH 


Arachidic 






CH 3 (CH 2 ) 18 COOH 


Behenic 






CH 3 (CH 2 ) 20 COOH 



These acids all conform to the general formula 

(C„H 2 „0 2 ). 

There are other fatty acids of the oleic or acrylic series that 
conform to the general formula 

(C n H 2n _ 2 2 ). 



FATS AND OILS 147 

II. These are Tiglic acid C 5 H 8 2 

Oleic C18H34O2 

Elaidic Ci 8 H 34 02 

Iso-oleic C18H34O2 

Erucic C22H42O2 

Brassidic C22H42O2 

The most important of these in medicine are oleic and tiglic — 
found in croton oil. 

III. The linolic series 

(CnH 2n - 4 2 ) 

1. open series linolic acid C18H32O2 

2. Chaulmoogric acid C18H32O2 

a cyclic compound, from chaulmoogra oil, which is used in the 
treatment of leprosy. 

IV. A linolenic acid series of the general formula 

C n H2 n -602 

is also known but not important in medicine. 

V. A clupanodonic series with the general formula 

C n H 2n -8 2 

VI. A ricinoleic oleic series, general formula 

C n H 2n _203 

of which the acid from castor oil is the important representative. 
While many of these are unimportant in medicine, they illustrate 
because of their unsaturated condition, what is meant by the 
iodine number — described below.. Unsaturated compounds as 
a rule are also more active physiologically than saturated 
compounds. 

The chief vegetable fats used in medicine are : 

Palm oil, which consists almost entirely of palmitin and cocoa 
butter, contains about 

40 per cent, stearin, 20 per cent, palmitin, 

30 per cent, olein, 6 per cent, linolein, 

Linseed oil consists mainly of oleins — a mixture of oleic, linolic, 
linolenic, and isolinolenic acids. 



148 CHEMICAL PHARMACOLOGY 

Cottonseed oil consists chiefly of olein, palmitin, and linolein, 
with small amounts of linolenic acid. 

Olive oil, consists of 72 per cent, of liquid glycerides, made 
up of olein 94 parts, linolein 6 parts, and about 28 per cent, 
palmitin. 

Castor oil consists mainly of the glycerides of triricinolein, 
together with ricinisolein, palmitin and dioxystearin. 

Croton oil: The composition of croton oil is very complex. 
The glycerides of at least 10 acids have been found, namely — 
oleic, palmitic, stearic myristic, lauric, valeric, formic, butyric, 
acetic, tiglic and croton oleic. It is a violent purgative, a single 
drop being a dose. When rubbed on the skin croton oil may also 
produce rubefaction and pustulation. It yields about half as 
much volatile fatty acids as butter, among these volatile acids are 
formic, acetic, and valerianic. While these acids are irritating, 
and it was formerly thought that the irritant and purgative 
action is due to the irritation caused by the acids liberated on 
saponification of the oil, it is now believed that these actions of 
croton oil are due to an acrid resin Ci 3 Hi 8 4 contained in the oil. 

Most oils are insoluble in alcohol, castor and croton oils are 
exceptions to this rule. Croton is somewhat soluble and castor 
is soluble in absolute alcohol. Both are soluble in ether. 

A distinguishing property of castor oil is its insolubility in 
petroleum ether. . It is likewise one of the heaviest fats having a 
specific gravity of 0.960 as against a range of 0.85 to 0.95 for 
other fats. 

Fats are extracted from seeds, or tissues after these have been 
thoroughly desiccated. They are then placed in extractors and 
the fat is drawn out with ether, light petroleum, carbon bisulphide 
or carbon tetrachloride. Ether is the usual laboratory solvent. 

These solvents extract also cholesterol, lecithin, essential oils, 
and the indefinite group of bodies known as lipoids, and the extract 
for this reason is known as the ether extract. A process of puri- 
fication must be employed if a pure product is desired. 

GENERAL PROPERTIES OF FATS 

1. The physical properties depend on the composition — oleins 
arc liquid, stearins are solid, palmitins of a vaseline or tallow 
consistency. 



ACTION OF SOAP 149 

2. Fats are insoluble in water and but slightly soluble in cold 
alcohol. 

3. They are soluble in ether, benzine, benzene, chloroform, 
carbon bisulphide, carbon tetrachloride. 

4. Fats can be heated from 200° to 250°C. without decomposi- 
tion. Higher heat may decompose them with the formation of 
the irritating volatile product of glycerine — acrolein 

CH 2 = CH- CHO 

This change is hastened by the addition of (KHS0 4 ) — potas- 
sium bisulphate, and is a test for true fats, or anything containing 
glycerine. 

5. Lipases hydrolyze fats into fatty acids and glycerine. This 
change may also be accomplished by bacteria and by superheated 
steam. Acids and alkalies greatly accelerate the reaction. This 
hydrolysis is known as saponification. 

6. When boiled with alkalies fats are hydrolyzed, and the 
combination of the alkali metal with the fatty acid is known as a 
soap. ' Green soap is the potassium or soft soap, and is so-called 
because the oils formerly used contained chlorophyll which gave 
the soap a green color. 

In medicine and pharmacy, antiseptics and other substances 
are frequently added to, or incorporated in the soap. These are 
the so-called medicated soaps. Cresol, thymol, tar, sulphur, 
mercury, salicylic acid, etc. are among the substances added. 
Castile soap is made from olive oil and sodium hydroxide; green 
soap from linseed oil and potassium hydroxide. Lead plaster is a 
lead soap. Resin and sodium silicate are added to soaps mainly 
as adulterants. Such soaps hold a great deal of water, hence 
weigh more than a pure soap, and this is the principal reason for 
the addition. 

Explanation of the Cleansing Action of Soap 

Ordinary soaps are the sodium potassium salts of fatty acids. 
These are weak acids, and their salts are decomposed to some 
extent by water just as sodium carbonate is, and soap solutions 
are alkaline in reaction for the same reason that sodium carbonate 
is alkaline. In water soap is hydrolyzed according to the formula : 



150 



CHEMICAL PHARMACOLOGY 



1. CH 3 (CH 2 ) 16 COONa->CH 3 (CH- 2 ) 16 COO + Na+ 

2. CH 3 (CH 2 ) 16 COO - + Na+ + HOH -> 

Na+ + OH CH 3 (CH 2 ) 16 COOH + 
Stearate ion Stearic acid 

Since stearic acid is insoluble in water, it is removed from solu- 
tion, and the NaOH ions react alkaline. The amount of free 
alkali depends on the dilution. In strong solution a soap that 
will cause just a pink color with phenolphthalein, may be dis- 
tinctly alkaline on dilution. These hydrolyzed products readily 
emulsify fats, and such emulsion is readily soluble in or removable 
by water. This briefly explains the mechanism of soap in wash- 
ing. Mathews explains the formation of these colloidal solutions 
as follows : 





II 
1. Na - - C - (CH 2 ) 1( 

Sodium stearate 



O 
CH 3 ^ |j 

Na+ + 0- - C - (CH 2 ) 16 - CH< 
i Sodium ion + stearate ion 






2. Na - O 







(CH 2 )i6- CH 3 + H 2 0^ 

NaOH+ H - - C - (CH 2 ) 

II 
O 

Stearic acid 



CH; 



3. Na+ - O - C - (CH 2 ) 16 - CH 3 + 2HO - C - (CH 2 ) 1( 

II II -CH 3 *: 



o 



+ 

Na + 



-o 

2HO 



C - (CH 2 )ie 
C - (CH 2 ) 16 





CH 3 

CH 3 



Colloidal soap. 

This negatively changed colloidal soap is held in solution by 
the great attraction of the positively changed sodium ion, for 



FAT CONSTANTS 151 

water, and it (colloidal soap) has a great attraction for the fatty 
acids of neutral fat or grease. Consequently when put on the 
skin, the fats of the skin adhere to the colloidal soap particles 
and are held in colloidal solution b} r the attraction of the sodium 
ion for water. Large easily removable aggregates may thus be 
formed. Vaseline, liquid petrolatum and other lipoids that do not 
form emulsions readily, are for this reason hard to remove. 

THE CHARACTERIZATION OF FATS 

The following methods are used for the recognition and the 
evaluation of fats. 

1. The melting point is determined. This shows the general 
nature of the fats — whether they are composed mainly of stearin, 
palmitin or olein. 

2. The acid number. This is the number of milhgrams of 
KOH required to neutralize the free acid contained in one gram 
of the fat. This is determined by dissolving 1 or 2 grams of the 
fat in about 20 cc. of a mixture of 1 part alcohol and two parts 
of ether. Titrate the solution with N/10 solution of KOH in 
alcohol. Alcohol is used here because water does not mix well 
with the oil, but causes an emulsion formation, and the end point 
is not clear. The acid number gives one an idea of the state of 
freshness of the fat. 

3. The saponification number or Koettstorfer number. The 
saponification number is the number of milligrams of KOH 
necessary to neutralize (to form a soap), with the fatty acids 
derived from 1 gram of fat. Since fatty acids are monobasic one 
molecule of potash neutralizes one molecule of acid, but each 
molecule of fat required three molecules of KOH— since glycerine 
esters or fats are tribasic. 

The saponification value is determined by dissolving a weighed 
amount of fat — about 2 grams — in a wide mouthed bottle 
holding from 250 to 300 cc. Add 25 cc. of half normal alcoholic 
KOH. Attach a reflux condenser and heat on a water bath for 
30 minutes. Cool and titrate the excess of KOH with semi- 
normal HC1, using phenolphthalein as the indicator. Sub- 
tracting the acid necessary to neutralize, from 25 cc. gives the 
saponification number. 

Since fats are glycerine in combination with monobasic fatty 



152 CHEMICAL PHAKMACOLOGY 

acids, the saponification number will give indirectly the molecular 
weight of the pure acid. This relationship is as follows: 

Mol. weight Saponification number 
Butyrin 302 557.3 

Palmitin 806 208.8 

Stearin 890 189.1 

Olein 884 190.4 

4. Unsaponifiable residue = Cholesterol and Phytosterol. 
These previous numbers are of value in the calculation of the 
molecular weight of acids only when we are dealing with pure 
products. The numbers however are of value in determining the 
nature of an oil, especially when taken in consideration with other 
constants. One of these is the amount of unsaponifiable resi- 
due. This residue consists mainly of cholesterols or phytosterols 
which are soluble in petroleum ether, while glycerol, and potas- 
sium hydroxide are not, and soap only slightly. Accordingly to 
determine the unsaponifiable residue, after saponification cool 
and filter off the soap — shake the solution with petroleum ether 
in a separatory funnel, and evaporate in a desiccator to constant 
weight, in a weighed dish. The residue represents the unsaponi- 
fiable residue. 

The following table gives the amount of unsaponifiable resi- 
due in the more important fats. 

Per cent, of 
Unsaponifiable Matter 

Lard 0.30 to 0.40 

Castor oil 0.30 to 0.40 

Human fat 0.33 to 0.00 

Linseed oil 0.42 to 1.00 

Olive oil 0.46 to 1.00 

Corn oil 1.35 to 2.90 

Wheat fat 4.45 to 0.00 

Shark oil 7.00 to 10.00 

Sperm oil 37.00 to 41.00 

Beeswax 52.00 to 56.00 

The isolation and identification of the unsaponifiable residue, 
is of importance in establishing whether or not a fat is of animal- 
or vegetable origin. 



IODINE NUMBERS 153 

5. The iodine absorption number of fats (Hiibls number) . This 
is the amount of iodine (per cent.) that a fat will absorb. 
It is a measure of the unsaturated fatty acids in the fat. An 
unsaturated (ethylenic) compound absorbs iodine after the man- 
ner of ethylene : 

C2H4 + I2 — >C2H4l2 

The resulting compound being saturated. 
To determine the iodine number the following solutions are 
needed. 

1 . 25 grams of pure iodine and 30 grams pure mercuric chloride, 
in 500 cc. pure alcohol, free from unsaturated compounds. 

2. A decinormal solution of sodium thiosulphate. 

3. Potassium iodid 20 per cent, in water, 

4. A 1 per cent, solution of starch paste as an indicator. 
The determination is made as follows : 

Weigh 0.3 gram of the fat in a glass stoppered bottle and dis- 
solve in about 20 cc. chloroform and add 25 cc. of the iodine solu- 
tion. Stopper the flask and set aside in the dark for 4 hours. 
Wash into a flask for titration, with 10 cc. of the KI solution and 
titrate with sodium thiosulphate solution. The difference be- 
tween the volume of thiosulphate needed and 25 cc. of iodine solu- 
tion used will be the amount of iodine absorbed or the iodine 
number. 

The reactions involved are: 

Each cc. N/10 thiosulphate represents 0.0127 gm. iodine 

I 2 + 2(Na 2 S 2 3 + 5H 2 0) = Na 2 S 4 6 + 2NaI + 10H 2 O 

The KI is added to prevent separation of the iodine in the 
solid state when diluted with water. The mercuric chloride 
forms : 

Hg.Cl 2 + I 2 = Hg.ClI + IC1 

The iodine chloride is perhaps the active agent in the addition, 
and facilitates the process. 

The iodine numbers of pure fats are : 

Olein 86.2 

Linolein 173.6 

Linolenin 262.2 



154 CHEMICAL PHARMACOLOGY 

Iodine Numbers of natural fats : 

Linseed oil 175-205 

Almond oil 145-150 

Olive oil '.......: 80-88 

Cottonseed oil 108-110 

Codliver oil .' . 107 

Neat's foot oil 67-73 

Palm oil 51 

Cocoanut oil 8-9 

Tallow 35-45 

Lard 50-70 

Butter .' 26-38 

Japan wax 4-10 

Spermaceti 0.4 

Unsaturation as evidenced by iodine absorption is a specific 
instance or kind of unsaturation and in no sense a general test 
for unsaturation. The unsaturation in the case of fats and oils 
is ethylenic — i.e. between carbon atoms. In aldehydes, ketones, 

R \ 

etc. which contain a carbonyl group ">C = O, there is also 

W 
unsaturation but iodine is not added to these. If hydrogen be 
used, however, it reacts with the carbonyl as also with the 
ethylenic linkage. 

The reactivity in the one case and not in the other is due to 
modification of the unsaturated bonds by attached molecules 
or atoms. This may be illustrated by the reactivity of the H 
atom in water, alcohol and acid. 

H.OH 
CH 3 CH 2 OH 
CH3COOH 

The difference in reactivity in each case being due to the modi- 
fying influence of the attached radical. 

THE HYDROGEN NUMBER AND HYDROGENATED FATS 

Under proper conditions hydrogen may be added to fats much 
in the same way as bromine. This changes ill-smelling and 



ACETYL VALUE 155 

tasting, cheap vegetable oils into more palatable products 
resembling the more expensive animal fats. The process of hy- 
drogenation is of great commercial importance. In some pro- 
cesses finely divided metals such as nickel are used as catalyzer, 
and some of the metal may remain in the finished vegetable lard. 
Nickel may be absorbed from the gastro-intestinal tract; and it 
is toxic, hence fats prepared in this way may be interesting from 
a pharmacological point of view. The pure products are not 
toxic, but if nickel remains in oil the latter may become toxic. 
These hydrogenated fats are important economically. 

THE REICHERT MEISSEL NUMBER 

This represents the number of cubic centimeters of N/10 KOH 
required to neutralize the volatile acids liberated from 5 grams 
of fat under certain special conditions. The process of determin- 
ing the amount consists in saponifying the fat with an alkali, then 
adding an excess of a non-volatile mineral acid, distilling and 
titrating the volatile acids. Phenolphthalein is used as the indi- 
cator. This method is especially useful in the examination of 
butter fat for adulteration. 

The Reichert Meissel numbers of the most important fats are : 

Linseed oil 0.0 

Goose fat 0.2 

Tallow 0.5 

Olive oil 0.6 

Lard 0.7 

Palm oil 5-7 

Cocoanut oil 6-7 

Croton oil 12-14 

Butter fat . . 25-30 

No other fat contains as much volatile acid as butter. 

THE ACETYL NUMBER 

This is a measure of the number of hydroxyl groups in a fat. 
The measurement of these depends upon the fact that substances 
containing the alcoholic hydroxyl group react with the acetyl 
group (CH3CO). The number of OH groups is arrived at by 



156 CHEMICAL PHARMACOLOGY 

treating the fat with acetic anhydride and heat; when a reaction 
takes place as follows: 

R. /CO — CH3 Rv 

)CHOH + c/ -> J>HC.OOC.CH 3 +CH 3 COOH 

W X CO - CH 3 W 

The acetyl derivative of the fat is stable in boiling water, and 
by boiling in water, excess of acetyl anhydride is converted 
into acetic acid. The acetylated fat can now be separated by 
filtration and washed free from the acid. This acetylated fat 
can be saponified according to the reaction: 

ROCOCH3 + KOH -> ROH + CH3COOK 

In this way the amount of potash required for the saponifica- 
tion can be used as a measure of the acetyl groups, and hence of 
the hydroxyl groups in the fat. 

The number of milligrams of potash required to neutralize the 
acetyl derivative of 1 gram of fat, is the acetyl value of that fat. 

The following table gives the acetyl value of some common 
pharmaceutic products: 

Linseed oil 0.4 

Olive oil 10.5 

Codliver oil '. 0.5 

Spermaceti 4.5 

Lard 2.6 

Tallow (Beef) 2.5-9 

Beeswax 15.0 

Wool wax 0.23 

Castor oil 0.15 

The Elaidin Test for Fats (Gr. Elais— Olive Tree) 

This test is distinctive for the oleic series. It depends on the 
fact that oleic acid is changed from the cis to the trans form on 
treatment with nitrous oxide, or liquid olein is converted into 
solid elaidin — which is an isomeride of olein. Other acids of 
this series are similarly transformed. 

The Elaidin test is performed as follows: 

(I) Place 10 cc. oil in a test tube and add 5 cc. nitric acid sp. 
gr. 1.38-1.40 underneath it. Place a small piece of copp'er (0.2 



TESTS 157 

gm.) in the acid. Leave at a temperature of not over 25°C. until 
the following day, and observe frequently or 

(II) 10 grams of oil are mixed with 5 cc. nitric acid sp. gr. 1.38 
and 1 gram of mercury, and the mixture shaken until the mercury 
is dissolved. Set aside and shake again after about 20 minutes. 
Note the time required for solidification. This reaction is called 
the "elaidic transformation." 

Depending upon the amount of oleic acid present, the oils 
vary in the length of time necessary for solidification. 

Olive oil solidifies in about 60 minutes. 
Peanut oil solidifies in about 80 minutes. 
Sesame oil solidifies in about 185 minutes. 
Rape oil solidifies in about 185 minutes. 
Lard oil — inside two hours. 
Linseed oil gives a red pasty froth. 
Hempseed oil remains unchanged. 

The temperature of the mixture should not exceed 25 degrees. 
At best the reaction gives only an idea of the character of the oil. 

The Bromine Test 

This test depends on the fact that linolic, linolenic and other 
unsaturated drying and semi-drying oils form insoluble addition 
compounds with bromine containing 6 or 8 atoms of this ele- 
ment, which is insoluble in ether. Linolenic acid having three 
double bonds yields a hexabrom derivative. The avidity of the 
reaction can be measured also by the heat of bromination, which 
runs parallel with the amount of bromine or iodine that a fat will 
absorb. To determine the amount of bromine absorbed: 1 to 
2 cc. of oil are dissolved in 40 cc. of ether and 2 cc. glacial acetic 
acid. Cool to about 5°C. and add bromine drop by drop until 
no more is absorbed. 

The precipitate is collected on a weighed asbestos filter and 
washed 4 or 5 times with ether, and dried in a steam oven. The 
weight is directly proportional to the amount of unsaturated 
acids in the fat. 

Maumene or Sulphuric Acid Test 

Fats of the linolic series on being mixed with sulphuric acid 
evolve heat while those of the oleic series do not. 



158 CHEMICAL PHARMACOLOGY 

The difference in degrees centigrade between the initial tem- 
perature and the temperature after the addition of sulphuric acid 
under special conditions is known as the Maumene Number: 
The test is carried out as follows :" 

Place a beaker of 150 cc. into a beaker of 800 cc. and pack the 
space between with cotton. Weigh 50 grams of oil into the smaller 
beaker. Place a thermometer in the oil and run in 10 cc. con- 
centrated H 2 S0 4 from .a burette at the same temperature as the 
oil. Stir the oil with the thermometer while the acid is running 
in. The temperature rises quickly, and remains at the high point 
a sufficient time to permit observation. The maximum point 
should be noted. The initial temperature subtracted from the 
maximum gives the Maumene number. 

RANCIDITY OF FATS 

Most fats but especially those containing unsaturated acids 
on exposure to the air become rancid and develop a disagreeable 
smell and taste. The unsaturated fatty acids are converted into 
others containing a smaller number of carbon atoms. Among 
the decomposition products aldehydes, alcohols, hydroxy acids 
and esters have been found. The actual cause of rancidity is 
but little understood. Oxygen, light, and heat, and moisture, 
facilitate the process which is probably initiated by enzymes and 
bacteria, while free acid is liberated in the process. 

Acids may be developed without rancidity as is often seen 
in cocoa butter which is frequently acid but rarely rancid. 

THE SIGNIFICANCE, USES AND FATE OF FATS 

Fat is found in varying amounts in all forms of living matter. 
This may not be seen in microscopic sections or when stained with 
sudan III, osmic acid and other fat stains but organic substances 
when extracted with ether and other fat solvents, always yield 
a lipoid residue on evaporation. After anesthesia for an hour 
with chloroform, sudan III shows that fat droplets are distinctly 
present in the cell, while chemical analysis shows that there is 
no greater amount than before the anesthesia. It is differently 
distributed after the anesthetic. 

In the economy of both plants and animals, fats are connected 



SIGNIFICANCE OF FATS 159 

with nutrition. They are readily stored and provide a food 
reserve which in animals is used in cases of food deficiency. 

They act as protectors to the proteins of the body, sparing the 
protein from oxidation. They also act as lubricants to the skin 
and aid in keeping it soft and pliable. If the lipoid material is too 
frequently and too vigorously removed from the skin, as is some- 
times done by the excessive use of highly alkaline soaps, the skin 
becomes dry and eczematous. In such cases the judicious 
use of oils externally is very beneficial. Many fats are used in 
emulsions for this purpose. Some fats because they are decom- 
posed into slightly irritating materials in the intestines are used 
as cathartics. 

In the protoplasm fats are distributed very finely as in milk. 
None of the ordinary fat tests will detect fat when it is so finely 
divided and protected. The fat in the cells in this condition may 
also act as a protective to the essential part of the cell. In phos- 
phorus poisoning and- in other conditions classed as fatty de- 
generations, the fat is run together and so loses its protective 
properties. In these conditions there is no increase in the actual 
body fat, but simply a redistribution of it. Why one person is 
fleshy — or the body retains a considerable amount of fat- — while 
another, is lean cannot be explained further than that the funda- 
mental properties of the protoplasm is different. This may de- 
pend on the physiological activity of some endocrine gland either 
acting on the seats of oxidation directly or through the nerves. 
It is known that basal metabolism is distinctly higher in hyper- 
thyroidism, and lower in hypothyroidism, and in other conditions. 

Oxidation furnishes the heat necessary for the body and fats 
are the heat producing foods par excellence, one gram of fat pro- 
duces 9.3 calories. Fats also act as a mantle and since they are 
poor conductors they aid in heat conservation by preventing 
evaporation and radiation. In cases of obesity this property 
may be a hindrance rather than a benefit. Fats also act as pack- 
ing material for such organs as the kidney, which is partially 
embedded and held in place by a cushion of fat. 

In plants fats are found in greatest amounts in the seeds and 
propagative organs. Their function here is protective, to pre- 
vent desiccation which would prevent germination, they also 
serve as nutritive material. Seeds contain lipases which may 



160 CHEMICAL PHARMACOLOGY 

either hydrolyse the fat into fatty acids and glycerine or syn- 
thesize the fats from the same materials. 

Regarding the origin of fat in the plant little is definitely known. 
In many cases there seems to be strong evidence that it originates 
from the carbohydrates. Certain seeds like the almond, and 
castor bean, and olive in the green state are rich in carbohydrates 
and poor in fats, but as they ripen the carbohydrate decreases 
and the fat increases. Glucose, sucrose, mannite, starch and 
other carbohydrates, have been observed to change in this way. 
Ivanow, in case of flaxseed represents the changes taking place 
as follows : 

^Glycerine . 

Carbohydrate ^ ")Fat. 

Saturated — -Unsaturated 
fatty acid fatty acid 

The reverse change is supposed to take place during germination. 
Miller found in case of the sunflower that the cotyledons in the 
resting state contained 1 per cent, free fatty acid while in the 
seedling there was 30 per cent, fatty acid. These fatty acids 
disappear, that is, are used by the plant in the following sequence; 
linoleic, linolic, oleic and finally palmitic; that is the more un- 
saturated acids are used first. There is some difference of opin- 
ion as to the changes in the original fat during germination, but 
one acid may be transformed into another. 

It has been suggested that starch may arise from oleic acid as 
follows: 

C 1S H 3 40 2 + 270 = 2(C 6 H 10 O 5 ) + 6C0 2 + 7H 2 

Fats may also arise from protein, but the proof of this is not 
so definite in the plant as in the animal. Fats may also be trans- 
ported in the plant from one region to another, similar to fatty 
infiltration in the animal. 

ORIGIN OF FAT IN THE ANIMAL 

1. It may arise from the fat of the food. Proof of this is found 
in (lie fact that when linseed oil, rape oil, mutton fat and the 
like arc fed to dogs— these fats ban be recognized in the fatty 
deposits of Hie tissues of the animal. Experiments have shown 



OKIGIN OF FAT 161 

that the fat of dogs fed on linseed oil, melts at 0° — while those 
fed on suet was solid at 50°C. 

2. From carbohydrates; animals have been fed on a carbo- 
hydrate diet, and the carbon retention has been shown to be in 
the form of fat. For example: Rubner fed a dog weighing 5.89 
kg. on starch, sugar, and fat that had a total carbon content of 
176.6 grams. During the period the animal excreted 87.1 grams 
of carbon, there was thus a retention of 89.5 grams. The fat 
of this diet had a carbon content of 3.6 grams. The animal ex- 
creted 2.55 grams nitrogen = 16 grams protein — (2.55 X 6.25). 
On the improbable assumption that all the carbon of this ex- 
creted protein was retained in the body, this would be 8.32 grams 
C (16 X 0.52) (52 per cent. C in proteins) so that 8.32 + 3.6 = 
12 grams, could originate from other sources than carbohydrate 
leaving 89.5 — 12 = 77.5 grams of carbon that could arise only 
from the carbohydrate and could be retained only as carbohy- 
drate or fat. The greatest possible amount of glycogen that 
could be stored from this would be 78 grams or 34.6 C so that there 
would still remain 42.9 grams of C that could be stored only as 
fat. This calculation is based on the fact that glycogen 
is stored equally between the liver and the muscles. The liver 
rarely exceeds 4 per cent, of the body weight and only in excep- 
tional cases will the liver glycogen = 17 per cent, of the weight 
of the organ. 

Numerous other fattening experiments have convinced physi- 
ologists that fats can be formed in the animal body from carbo- 
hydrate. The chemistry of this change is not understood, and 
cannot be imitated in the laboratory. See Lusk, Science of 
Nutrition, 3d Edition. The following hypotheses have been 
proposed in that the process starts with pyruvic acid. Lactic 
acid arises from the sugar and may be converted into pyruvic 
acid by oxidation. The pyruvic acid unites with an aldehyde to 
form higher fatty acids : 

I. R CHO + CH 3 CO COOH = R CHOH CH 2 CO COOH. 

II. R CHOH CH 2 CO COOH + = R CHOH CH 2 COOH -f 

C0 2 and 

III. R CH 2 CH 2 COOH. 

may also be formed on further oxidation. 
11 



162 CHEMICAL PHARMACOLOGY 

This gives some idea of how higher fatty acids may be formed 
in the plants. The glycerol necessary to form fat from the fatty 
acid may be synthesized in the plant in a manner unknown to 
the chemist. That it may be formed from the elements has been 
shown by Friedel and Silva through the following steps : 

CH3COOH -+CH 3 CO.CH 3 ^ 

Acetic acid Acetone 

CH3.CHOH.CH3 -+CH 3 .CH:CH 2 
Propyl alcohol Propylene 

CH3.CHCl.CH2Cl->CH2Cl.CHCl.CH 2 Cl-> 
Propylene chloride Trichlorhydrin 
CH 2 OH.CHOH.CH 2 OH 
Glycerol 

FATS FROM PROTEINS 

It has been shown quite definitely in feeding experiments that 
fat may be formed from protein. There has been considerable 
difference of opinion on this question. Pettenkoffer and Voit 
claiming a distinct formation while Rubner questioned the com- 
putation on the basis that they had used the ration of carbon to 
nitrogen in protein as 3.68 instead of 3.28 which he believed to 
be the correct figure. Cremer, however, showed by experiment 
that fat may be formed from protein and his results have been 
amply confirmed. His experiment is as follows: 

A cat was starved for a number of days. It was then fed 450 
grams of meat a day. The animal was kept in a ' respiration 
chamber and the C0 2 in respiration measured and the excreta 
analysed. There was a daily excretion of 13.0 grams nitrogen — 
41.6 grams of protein carbon (13 X 3.18). However only 34.3 
grams of carbon was eliminated. 7.3 grams or 17:5 per cent, of 
the carbon taken in was retained. In 8 days 58 grams of carbon 
was retained. If this were stored as glycogen it would make 130 
grams, but in the total animal at this time there was found only 
35 grams of glycogen. The balance must have been stored as fat. 

This subject has also been investigated by Atkinson and Lusk 
who have shown by calculations based on respiratory quotients 
and heat production as measured by the respiration calorimeter 
that fat is produced from protein in the dog after the ingestion 
of large quantities of protein. 



ORIGIN OF FATS 163 

THE NEED OF FATS IN GROWTH 

The normal growth of an animal depends upon something in 
addition to the requisite number of calories of fats, proteins and 
carbohydrates. The fat must be of a certain source and contain a 
growth promoting substance "A," or what has been called vita- 
mine. All fats do not contain this vitamine. It is especially 
abundant in butter fat, beef fat, egg yolk, and cod liver oil. 
Animals fed on a diet in which olive oil or almond oil supplies the 
fat, do not grow, and soon will die if such diet is continued. 
However, even when death is near, the substitution of vitamine 
containing fat, immediately restores normal health and growth. 
The nature of this substance is not known. The term vitamine, 
suggests that they are amines, but such is not the case. The term 
vita, McCollum thinks, gives an importance to these essentials, 
greater than other equally indispensable constituents of the 
diet. He suggests until more definite knowledge is obtained, the 
term fat soluble "A" be applied to the vitamine essential growth 
promoting ingredient of fats, and to other like substances which 
are soluble in water, water soluble "B. " 

THE FATE OF FATS IN THE BODY 

Fats are easily and completely oxidized in the body and are a 
great source of body heat. They are absorbed after saponifica- 
tion and resynthesized again in the body, probably by an enzyme. 
In the dog 10-20 per cent, of the fat of a meal is absorbed in four 
hours, about 30 per cent, in seven hours and 86 per cent, in 18 
hours. After excision of the pancreas, or disease of it, fat ab- 
sorption is markedly retarded but not abolished. 

In man the feces contains 0.5 to 1.5 grams of fat in starvation, 
while on ordinary diet containing about 120 grams fat, 3 to 7 
grams is excreted. 

Normal urine contains no fat, but in diseased conditions 
variable amounts may be found. The condition is known as 
lipuria and may occur after excessive eating of fat, after cod 
liver oil, in fat embolism occurring after fractures, in phosphorus 
poisoning and other fatty degenerative processes, in prolonged 
suppuration, chronic Bright's disease, diabetes, chronic alco- 
holism, in wasting diseases, diseases of the pancreas, obesity, 
leukemia, and in mental diseases. 



164 



CHEMICAL PHARMACOLOGY 



XVIII. WAXES 

The waxes are esters of higher monatomic alcohols or sterols 
such as cetyl alcohol, Ci6H 33 OH, myristic alcohol, C 3 oH 6 iOH, 
or cholesterol C27H45OH, and one of the higher fatty acids. 
Spermaceti is a wax, obtained from a cavity in the head of the 
sperm whale, and consists mainly of cetyl alcohol and palmitic 
acid or cetyl palmitate. Bees wax consists chiefly of myricil 
alcohol and cerotic and melissic acids in ester combination. 

Waxes are of both animal and vegetable origin. The surfaces 
of all organisms, both plant and animal, are covered with a layer 
of wax. The secretion is found in greater abundance in some 
plants than others. The function of it is to protect the plant or 
animal from over-wetting or over-drying and against changes in 
temperature. For these reasons waxes are important in the pro- 
tection of the eggs and larvae of insects. It is well known that 
wax is a poor conductor of heat as well as electricity. 

Lanolin or wool fat, or more correctly, wool wax, consists 
largely of monatomic alcohol, cholesterol in the free state. There 
is also some of this combined with myristic, cerotic, and lanoceric 
acids to form true wax. 

The fact that waxes generally have a harder consistency than 
fats has given rise to incorrect nomenclature in some cases. For 
instance, wool fat, which is in reality a wax, is not usually re- 
garded as such, while Japan wax, produced by a species of Rhus, 
is actually a fat. True fats are esters of glycerine, but waxes 
are esters of higher fatty acids and monatomic alcohols. There 
is a great variation in the alcohols and the fatty acids in waxes 
as the following list will show: 

(Composition op the Waxes — Taken prom Mathews Physiological 
Chemistry, 1915, p. 80.) 






Acids. Saturated. 


Formula 


Melting point 


Wax 




C13H2CO2 
C14H28O2 
CUH32O2 
C24H4MO2 

C20HG2O2 
C30HC0O2 

C23Hoo02 


57°C. 
53.8° 
62. & 
72.5° 
77.8° 
91° 
94-95° 


Gundang. 




Wool. 




Bees. Spermaceti. 




Carnauba. Wool. 




Bees. Wool. Insect. 








Psylla. 







STEROLS 



165 



II. Acryllic series. 

Physetoleic 

Doeglic (?) 

Lanopalmic 

Cocceric 

Lanoceric 

III. Alcohols. Sterols 

Pisan ceryl 

Cetyl (Ethal) 

Octodecyl 

Carnaubyl 

Ceryl 

Myricyl (Melissyl) 

Psyllostearyl 

Lanolin alcohol 

Ficoceryl 

Cholesterol 

Cocceryl 

Iso-cholesterol 




Sperm oil. 
Sperm oil. 
Wool. 

Wool. 



Ci 


6H340 


c, 


eHseO 


CisHssO 


C24H50O 


C26H54O 


C30H62O 


C33H58O 


Ci 


2H24O 


C17H280 


C27H460 


C30H62O2 


C26H460 



78° 

50° 

59° 

68-69° 

79° 

85-88° 

68-70° 

102-104° 

198° 

148.4-150.8° 

101-104° 

137-138° 



Pisang. 

Spermaceti. 

Spermaceti. 

Wool. 

Wool Chinese. 

Bees. Carnaubf 

Psylla. 

Wool. 

Gundang. 

Wool. 

Cochineal. 

Wool. 



Waxes are soluble in the ordinary fat solvents, benzene, ether, 
chloroform, etc. but are less soluble than the fats. 

When heated, waxes give no smell of acrolein, since they contain 
no glycerine. They are saponifiable like the fats, but with more 
difficulty. 

STEROLS 

These are solid alcohols, "steros, " meaning solid, and "ol" 
the chemical ending signifying, alcohol. Cholesterol C27H45OH 
was the first discovered member of the group, and the most im- 
portant. It is a secondary alcohol, since it oxidizes to a ketone. 
Compounds closely related to cholesterol are found in plants, 
phytosterols, and also in feces, coprosterols. 

Cholesterol can be taken as a type of the sterols, which are 
important as constituents of waxes. The relation of the sterols 
to waxes is the same as glycerine to fats. 

CHOLESTEROL 

This sterol was first prepared from gall stones in 1785 by Four- 
croy and studied by Chevreul in 1814, who named it cholesterin 
from the Greek chole, bile, and steros, solid. Some gall stones 
are almost pure cholesterol. It is also found in brain tissue. 
The important source of it is lanolin or wool fat, "lana " 



166 CHEMICAL PHARMACOLOGY 

wool, oleum, oil, or adeps lanse hydrosus. This contains some 
free cholesterol and some combined with myristic, cerotic, lano- 
ceric, and lanopalmitic acids in the form of wax. Wool wax also 
contains other sterols, as carnabuyl, and lanolin alcohols. 

Cholesterol is insoluble in water and alkalies, sparingly soluble 
in cold, but readily soluble in hot alcohol, ether, acetone, chloro- 
form, and other organic solvents, slightly soluble in soap solutions 
and much more soluble in solutions of bile salts. It is readily 
soluble in oleic acid and oils. Solutions of it react neutral. It 
is tasteless, odorless, cannot be saponified, and is remarkably 
stable toward oxidation. These reasons, and the additional one 
that it does not become rancid, recommend its use in ointments, 
etc. Because of its penetrative power, it is used as the base to 
carry drugs through the skin. 

Cholesterol is found to some degree in every cell, probably as a 
protective agent. The structure of it is not satisfactorily known. 
Mauthner 1 assigns to it the following formula : 
CH 3 . 

/CH.CH2CH2 - C17H26CH: CH2 

ch/ /\ 

H 2 C CH 2 



CH(OH) 
Windaus 2 gives 

CH a . 

/CH — CH2 — CH2 — C11H17 



CH 



CH CH 

H 2 C CH CH - CH 3 

I I I 
H 2 C CH 2 CH 



c\ || 
HOH CH 2 

From these formulas it is seen to be closely related to the 
terpenes, which are also important in drug chemistry. 

1 Zeit. f. physiologischc cliemic, 1901, 34, 426. 

2 Ber. Deutsche, chem. gesellschaft, 1912, 45, 2421. 



CHOLESTEROL 167 

This constitution is not yet definitely settled. It is evidently a 
terpene compound. The formation of terpenes in the animal 
body is hard to explain, and it seems probable that it does not 
originate in the animal organism. Animal cholesterol is ap- 
parently plant cholesterol, utilized by the body. ] The metabol- 
ism of it in the body is as unknown, as is its function, though it 
possesses certain definite properties which are pharmacologic 
importance. Lecithin accelerates the activity of cobra poison 
and cholesterol retards the action of lecithin. Snake venom 
added to washed red blood corpuscles suspended in water, will 
not cause laking. If, however, a trace of lecithin be added, laking 
results. A trace of cholesterol dissolved in methyl alcohol will- 
neutralize the influence of the lecithin in this case. Since lecithin 
and cholesterol exist in all cells and especially in red blood cor- 
puscles, it seems that the function of the cholesterol is protective. 
Preparation and Tests for Cholesterol 

Place 2 grams of wool fat in a 100 cc. Erlenmeyer flask, add 
25 cc. of 25 per cent, alcoholic (KOH) and boil under a reflux 
condenser for two hours with frequent shaking. This saponifies 
the fats but not the cholesterol. Pour the mixture into an eva- 
porating dish and evaporate off the alcohol. Dissolve the resid- 
ual soap in 50 cc. of hot water and transfer to a 200 cc. separating 
funnel, cool and add 50 cc. of ether and shake several times. 
The ether dissolves the cholesterol. If separation does not occur 
readily, add 5 cc. alcohol and shake again. Run off the soap 
solution and collect the ether solution in a dry evaporating dish 
and evaporate to dryness on a water bath. 

1. Examine the residue under a microscope on a glass slide for 
the characteristic crystals. 

2. Cholesterol on oxidation yields pigments. The Lieber- 
mann-Bur chard test is the most delicate and characteristic. 
The test is as follows : 

Dissolve a few crystals of cholesterol in 2-3 cc. of chloroform in 
1 Recently, Gamble and Blackfan (J. Biol. Chem., 1920, 42, 401-9), 
from analysis of the non-saponifiable fraction of the feces of undernourished 
children for three days found the excretion of cholesterol larger than the 
amount in the food. They interpreted this result as indicating a synthesis of 
cholesterol in_the body. This is confirmation of an older observation of 
Mueller, but does not satisfactorily account for the excretion of a probable 
storage from previous feeding. 



168 CHEMICAL PHARMACOLOGY 

a dry test tube or in the depression of a test tablet. Add about 
10 drops of acetic anhydride, shake and add concentrated H 2 S0 4 
drop by drop. A transient pink color first develops, which on the 
addition of more acid changes to blue and finally to green. 

3. Schiff's reaction: A few crystals of cholesterol are placed 
on a porcelain dish and treated with a few drops of a mixture of 
1 volume 10 per cent, ferric chloride and 3 volumes of concen- 
trated H 2 S0 4 . It is then evaporated carefully to dryness over a 
free flame. A reddish violet residue changing to bluish is 
obtained. 

4. Crystals of cholesterol on a white surface, when moistened 
with a mixture of 5 parts H 2 S0 4 and 1 part water, turn pink. 
On the oxidation of a drop of very dilute solution of iodine a play 
of colors violet, blue, green, and red, results. 

All animal fats contain cholesterol while vegetable fats con- 
tain phytosterol, and sitosterol. The isolation and identification 
of the unsaponifiable residue, therefore, is of considerable im- 
portance, in establishing whether or not a fat is of animal or 
plant origin. In food products the more expensive animal fats 
are sometimes substituted by or adulterated with, the cheaper 
vegetable fats. Recently vegetable fats have been hydrogen- 
ated to make them more nearly like animal fats — see p. 154, but 
such hydrogenated fats are used only as foods. 

XIX. VOLATILE, ETHEREAL OR ESSENTIAL OILS 

The sources of the volatile oils are mainly the flowers, fruit 
and leaves of many plants. They differ from the fixed oils 
chemically, physically, pharmacologically, . and economically. 

The composition of volatile oils is very variable and not fully 
understood. Terpene is the most common constituent. Many 
are composed mainly of terpenes either of the aliphatic or aro- 
matic series. But mixtures of terpene derivatives which include 
alcohols, aldehydes, ketones, acids, esters, ethers, phenols, lac- 
tones, quinones, oxides, nitrogen and sulphur compounds occur. 
Some non-terpene hydrocarbons have also been found and in 
some oils no terpene has been found (Attar of Roses). The 
only common characteristic of the volatile oils as a class is their 
volatility. They all contain hydrogen and carbon and most of 
them also oxygen. A few contain nitrogen or sulphur or both. 



TEKPENES 169 

The characteristic odor of the oil is associated with the oxygenated 
part of the molecule, and especially with the oxygenated aliphatic 
terpene. 

CHEMICAL CLASSIFICATION 
Dumas in 1833, classified volatile oils as follows: 

1. Those containing carbon and hydrogen only, like turpen- 
tine. 

2. Those that contain oxygen, like camphor and eucalyptus. 

3. Those that contain sulphur, like mustard oil or 

4. Nitrogen, like oil of bitter almonds. While this classifica- 
tion may still be used in a modified form, it is to general to give one 
any information regarding the composition of any volatile oil. 

ALIPHATIC HYDROCARBONS IN VOLATILE OILS 
Heptane C 7 Hi 6 is the lowest member of this series found in 
volatile oils. It has been found in the distillate of the oleoresin 
of some California pines. Higher members of this series and of 
the olefin series occur quite generally in the wax-like secretions 
of leaves, flowers and fruits. They occur mixed with other 
homologues and not as pure products. Octylene C 8 Hi 6 has been 
found in the oils of bergamot and lemon. A number of terpene 
hydrocarbons have been isolated. 

TERPENES 
Terpenes were formerly defined as hydrogenated derivatives 
of cymene and its substituted products (true terpenes). More 
recent work however has discovered some olefine terpenes. 
These can readily be converted into aromatic terpenes. All 
terpenes are unsaturated compounds and can be hydrogenated 
readily and yield addition products with halogens. On exposure 
to the air they are oxidized to resins, and this has given rise to 
the opinion that natural resins are oxidized products of volatile 
oils. As a group they appear to be derived from hydrocarbons 
of the composition C 5 H 8 . They are classified as: 

Hemiterpenes .' . C 5 Hs 

Terpenes Ci Hi 6 

Sesquiterpenes Ci 5 H 2 4 

Diterpenes C 2 oH 32 

Polyterpenes * (C 5 H 8 )n 

These may be divided into two groups: 
1. The olefine terpenes. 



170 CHEMICAL PHARMACOLOGY 

2. The aromatic terpenes. 

(a) Monocyclic. 
(6) Dicyclic. 

The monocyclic are represented by cymene or menthol and the 
dicyclic by camphor and camphane. 

The most important terpenes of the aliphatic or olefine series 
are: 

CH 2 v /CH 3 

\ C— CH 2 — CH 2 — CH 2 — CH<^ 
CH 8 X CH 2 — CH 2 OH 

Citronellol (Lemon oil) 
CH 3x z CH3 



)(J> — CH — CH 2 — CH 2 — Cj 



/ 

CH 3 X ^CH— CH 2 OH 

Geraniol (Oil of geranium) 

CH3V /CH3 

)C=CH— CH 2 — CH 2 — C^CH=CH 2 
CH/ X OH 

Linalool (Oil of lavender) 
CH K >CH 2 



;C — CH — CH 2 — -CH 2 — C 



y 



CH/ \}H=CH 2 

Myrcene (Oil of lignaloes, etc.) 

CH 3 v /CH 3 

CH 

The nucleus of true terpene 
is cymene 



CH 3 

or paramethyl isopropyl benzene, which can be derived easily 
from some of the volatile oils, stearoptenes and camphors. 

C 10 Hi 6 O + P2O5 -> C 10 H^ 4 + H 2 

Camphor Cymene 

CioHie + O^doHu + H^ 
Turpentine Cymene 



AROMATIC" TERPENES 171 

Cymene is a pleasant smelling liquid — specific gravity 0.87 
and boils at 175-176°C. On oxidation with dilute HN0 3 the 
isopropyl end of the ring is first oxidized and para toluic acid is 
formed CH 3 .C 6 H 4 .COOH. Further oxidation yields terephthalic 
acid COOH.C 6 H 4 COOH (1 :4). In the body the methyl end 
of the chain is first attacked and cumic acid is formed : 

/ CH(CH 3 ) 2 

X COOH 

Cumic acid 

and excreted as the glycocoll conjugate, cuminuric acid 
(CH 3 )2CH.C 6 H 4 CO.NH.CH 2 COOH 

AROMATIC TERPENES 

True ter penes have the formula Ci Hi 6 . They seem to be 
polymerides of the hemi-terpene (C 5 H 8 ). Two or more mole- 
cules of this compound may polymerize to form terpenes or 
polyterpenes. 

In the destructive distillation of india rubber, or when tur- 
pentine is passed through a tube heated to redness, isoprene 
(C5H3) which is methyl divinyl, is formed 

CH 3x CEL 

f^ CH 2 . 



CH 



This is a liquid B.P. 37°. It polymerizes readily to the 
terpene dipentene, 

CH 3 v CH 3 v ,CH — CH . 

2 X C— CH = CH 2 -> ^0— CH^ \C.CH 3 

CH2 CH.2 CH2 — CH.2 

Isoprene Dipentene 

On treatment with acids, isoprene polymerizes, forming rubber 
again, which is considered as a resin. 

The terpenes may be considered as being derived from iso- 
prene or an isomeric hydrocarbon. The true terpenes all con- 
tain the dipentene or cymene nucleus. 



172 



CHEMICAL PHARMACOLOGY 

CH 3 CIL 



Cymene 
nucleus 



Dipentene 
nucleus 



C 

/\ 
CH3 CH3 



c 

CH2 CH; 



The terpenes being unsaturated bodies, unite with HC1 or 
HBr to form addition products. The unsaturated condition 
also imparts great reactivity to them. They absorb oxygen 
readily and resinify. HN0 3 or iodine and other oxidizing sub- 
stances mixed with them may cause explosions. Weaker oxidiz- 
ing may break them down with the formation of acetic, propionic, 
butyric, oxalic, and other acids while bromine and iodine convert 
them into cymene. One of the easiest ways to prepare cymene 
is to treat camphor with P 2 S5,ZnCl 2 , or P 2 5 (p. 170). 

The main characteristics of this ill-defined group of true 
terpenes are: 

1. Their composition Ci Hi 6 . 

2. Their unsaturated condition. 

3. Their great reactivity. 

4. Their tendency to polymerize and resinify. 

5. On reduction they yield hydroterpenes. 

6. On oxidation with potassium, they yield, in many cases, 
benzene derivatives. 

7. The presence of the cymene ring or nucleus. 

8. They boil without decomposition at 155-180°C. 

9. When taken into the body, they as a rule, are excreted 
combined with glycuronic acid, as conjugated glycuronates. 

For convenience of study, the true terpenes have been sub- 
divided as follows: 

1. The terpenogen group 

2. Tcrpan or menthan group 



VOLATILE OILS 173 

3. Camphan group. 

Group I. consists of alcohols, aldehydes, acids, etc., combina- 
tions of terpenes from which the hydrocarbon can readily be 
prepared. 

Group II. Menthol is a prominent member of "this group, 
and has certain reactions which distinguish it from the first group. 
It is not so easily converted into the hydrocarbon. 

Group III. Camphor is the typical representative. Cam- 
phor yields camphene which is the only solid terpene known. 

ALIPHATIC ALCOHOLS IN VOLATILE OILS 

Methyl alcohol occurs frequently and has been found in aque- 
ous distillates of the oils of cypress, savin, vetiver, orris, etc. 
Ethyl alcohol has been observed only in a few instances. N 
butyl, isobutyl, isoamyl, n hexyl, heptyl, n octyl, n nonyl and 
undecyl have also been found. Various other less known alipha- 
tic alcohols have been reported. 

AROMATIC ALCOHOLS IN VOLATILE OILS 

Benzyl, phenyl ethyl, phenyl propyl, and cinnamic occur; 
also salicyclic alcohols, are more or less commonly found. 

DIFFERENCES BETWEEN FIXED AND VOLATILE OILS 

The chief differences are: 

Fixed Oils Volatile Oils 

1. Leave a greasy spot on paper. Evaporate completely. 

2. Can be saponified. Cannot be saponified. 

3. Will not explode when May explode when brought 

brought together -with ni- together with nitric and 

trie acid, iodine, or other other oxidizing agents, 
oxidizing agents. 

4. Chemical composition — esters Chemical composition, 

of glycerine and fatty acids mainly terpenes and deriv- 
atives. 

5. Almost insoluble in alcohol, Soluble in ether, chloroform, 

except castor oil. Soluble benzene, and other oils, 
in ether, chloroform, ben- 
zene, and in other oils. 



174 CHEMICAL PHAEMACOLOGY 

6. More easily emulsified. Not so easily emulsified. 

7. Used in medicine as laxatives, Used in medicine as flavors, 

emollients, vehicles for oint- carminatives, stomachics, 
ments, liniments, etc. correctives, rubifacients, 

deodorants, antiseptics, etc. 

8. Are foodstuffs. Are not foodstuffs. 

9. Completely oxidized in the Not oxidized but are excreted, 

body and excreted as C0 2 mainly combined with 
and H 2 0. glycuronic acid. 

THE GENERAL ACTION OF THE VOLATILE OILS 

All volatile oils attack protoplasm and are antiseptic for this 
reason. This is a general action of benzene derivatives, and most 
volatile oils are such. The volatility of the oil aids in its penetra- 
tion and action. When applied to the skin, they produce itching, 
redness, some anesthesia, and if volatilization be prevented they 
will cause blistering. The turpentine stupe, which is essentially, 
oil of turpentine, sprinkled on a woolen cloth wrung out of hot 
water, and applied to a part of the body, gives one a good idea of 
the local action of volatile oils. Some oils, such as oil of mustard 
act after they are broken down into active ingredients, and others 
such as menthol have a specific action on the nerves conveying 
the sensation of cold. In general however the action resembles 
that of turpentine. 

Action on the Alimentary Tract 

Oils generally have an agreeable taste. They are slightly 
irritating and cause a flow of saliva. They are readily absorbed 
and may increase the appetite. When swallowed small doses in- 
crease moderately the activity of the gastro-intestinal tract and 
act as carminatives. Excessive doses produce symptoms of 
inflammation with vomiting and diarrhoea. 

The oils circulate in the blood for the most part unchanged, 
but due to their action on the intestine a leucocytosis may be pro- 
duced. If very large doses are taken the central nervous system 
is influenced and convulsions may occur. This is readily demon- 
si rated by giving rabbits large doses of camphor which acts like a 
volatile oil. The harmful effects of absinthe (a volatile oil) are 
due to its action on the central nervous system. The continued 






GLYCURONIC ACID 



175 



use of any volatile oil may lead to fatty degeneration of the liver 
and kidneys. 

Volatile oils are excreted mainly in combination with glycu- 
ronic acid — as glycuronates, but this is not characteristic as many 
other substances are excreted in this way. 

Substances Excreted Combined with Glycuronic Acid. — In ad- 
dition to terpenes the following substances, when ingested, may 
be excreted as glycuronates: 



Isopropyl alcohol 


Chloral 


Methylpropyl carbinol 


Butylchloral 


Methylhexyl 


carbinol 


Bromal 


Tertiary butyl alcohol 


Dichloracetone 


Tertiary amyl alcohol 




Pinacone 






Saccharin 






Benzene 


Turpentine oil 


Nitrobenzene 


Camphor 


Aniline 


Borneol 




Phenol 


Menthol 




Resorcinol 


Pinene 




Thymol 


Antipyrine 


a-and /3- 


Etc. 




naphthol 







The Significance of Glycuronic Acid in the Urine 

In the normal metabolism of glucose, the aldehyde end of the 
chain is first oxidized. Glycuronic acid is formed from glucose 
by oxidation of the CH 2 OH end of the chain. It is thought by 
some to be formed in small quantities in normal metabolism, 
but this does not seem to be correct, since glycuronic acid 
administered parenterally appears in the urine quantitatively 
(Biberfeld, 1914). Its appearance in the urine following the 
administration of drugs indicates a derangement of carbohydrate 
metabolism. The formation of the glycuronic acid may be due 
primarily to the drug uniting with the aldehyde end of the 
chain which prevents its oxidation. 

According to their uses in medicine volatile oils may be classi- 
fied as: 



176 CHEMICAL PHARMACOLOGY 

1. Flavoring agents or carminatives: 

Cloves Peppermint 

Coriander Rose 

Lavender etc. 

Lemon 

2. Malodorous oils, used mainly for their psychic effect: 

Asafcetida 
Valerian 

3. Genito-urinary disinfectants. All volatile oils are mildly 
antiseptic but those especially valuable here are : 

Copaiba 

Cubebs 

Sandalwood. 

Tests 
Any fixed and volatile oil may be used. Oil of turpentine is 
taken as a representative of the volatile oils and cottonseed as 
a type of the fixed oils. 

1. Place a drop of each on a piece of glazed paper and note the 
difference. 

2. Test the solubility of each in water, alcohol, and acetic 
acid, chloroform. Repeat this, using croton or castor oil. 

3. Add 1 cc. of oil of turpentine to water in a test tube, shake 
and let settle. Draw off the water and note the odor. What are 
aquae? 

4. Saponification. — In an extractor place 200 cc. of cotton- 
seed oil and 100 cc. of 10 per cent, alcoholic solution of KOH. 
Heat on water bath for 30 minutes, cool and add 15 grams of 
NaCl in 50 cc. of water. This converts the soft green soap into 
hard soap. Green soap (sapo viridis) was so named because the 
vegetable oil from which it was first prepared contained enough 
chlorophyll to color it green. Soft soap as now prepared is not 
colored green. 

5. Heat a little fixed oil with a crystal of KHSO4 in a test 
tube over a free flame. Note the odor of acrolein (acer, 
sharp and oleum, oil). Repeat, using glycerine instead of oil. 

CH 2 OH.CH 2 OH.CHOH - H 2 0-> CH 2 :CHCHO 

Glycerine Acraldehyde or acrolein 

Fats and oils become rancid on standing, especially when ex- 



STEAKOPTENES 177 

posed to light, of if there is a small amount of protein present. 
For this reason in the preparation of ointments, benzoinated 
lard, lanolin, or petrolatum is often substituted. 

Lanolin or wool fat, C27H45OH, is cholesterol, a monatomic 
alcohol obtained from sheep's wool. It resembles fat in appear- 
ance and solubility, and does not become rancid, but is expensive. 
It is used in plasters and ointments. 

The cholesterols are closely related to the terpenes. 

STEAROPTENES 

Stearoptenes from their pharmacological action may be con- 
sidered as solid volatile oils. When volatile oils are allowed to 
stand at low temperatures, they separate into two layers. The 
top or lighter layer is known as eleoptene and the lower crystal- 
line deposit, as stearoptene. The latter is an oxidized product 
of the oil. Camphor, menthol, and thymol are the most impor- 
tant stearoptenes. Some unimportant stearoptenes are liquid 
at ordinary temperature. 

Camphora or camphor is a saturated ketone derived from 
cinnamomum camphora. It is said to be saturated because it 
will not form addition products. It has the formula — Ci Hi 6 O. 
The form of camphor in white masses of crystalline structure 
which have the same solubilities as the volatile oils. 




CH 3 

Camphor-menthol of the National Formulary is a solution pro- 
duced by triturating equal amounts of camphor and menthol. 
Its uses are as an antiseptic, and as a local anodyne. 

Camphor monobromata Ci Hi 5 Br.O is a substitution product 
of camphor. It occurs as prismatic needles or scales, the solu- 
bility being the same as camphor. Borneol camphor: CioHieO is 
a secondary alcohol obtained from ordinary camphor by reduc- 
tion. 

C 9 H 16 CO + 2H = C 9 H 16 CHOH 
Camphor Borneol-camphor 

12 



178 CHEMICAL PHARMACOLOGY 

Camphor is oxidized in the body to camphorol, 
CioH]60 — > C10H15O.OH 

This then combines with glycuronic acid and is excreted as 
the glycuronate 

C 10 H 15 O.OH + C 6 Hio0 7 = CioH 15 O.C 6 H 9 6 + H 2 

The camphors are used in medicine chiefly in liniments and 
for stimulation of the respiratory and circulatory centres, as 
well as the heart muscle in threatening collapse. Externally as 
a liniment, camphor irritates the skin and dilates the vessels. 
It is used therefore as a rubifacient. It has a mild antiseptic 
action and is used to keep away insects. Camphor vapor is a 
mild paralyzer of all undifferentiated protoplasm. When taken 
by mouth it has a warm bitter taste and carminative action, 
much like the volatile oils. Large doses may cause nausea and 
vomiting. If large doses are taken it may be absorbed and if so 
has a definite stimulant action on the central nervous system, 
much like the volatile oils. 10 cc. per kilo of body weight of a 
20 per cent, solution of camphor in olive oil given to a rabbit will 
produce peculiar bucking spasms in which the animal may turn 
a sommersault backwards. 

Menthol. — C10H22O. Menthol is a secondary alcohol de- 
rived from peppermint-men tha piperita. It occurs in crystals or 
prisms, the solubility of which is the same as the volatile oils. 
The dose is about 1 grain, and it is used as an antiseptic, analgesic 
and stimulant. 

H3C CH3 



C— H 

I 
C— H 

H 2 =C C— H OH 

H2 == C CH2 

V 

CCH3 

I 

H 

Menthol 



THYMOL 179 

Thymol is a phenol from the oil of thyme. It occurs in large 
translucent rhombic prisms, its solubilities in general being the 
same as the other stearoptenes. It is used especially in the 
treatment of hookworm disease, also as an antiseptic and anti- 
pyretic. 

Thymolis Iodidum. — Aristol-thymol iodide is a condensation 
product consisting of two molecules of thymol containing iodine 
in the phenolic groups. It is a reddish yellow powder and is 
used for the same purposes as iodoform, i.e. antiseptic. 

Menthol has many of the actions of camphor. It is much used 
as a nasal spray, 1 per cent, menthol in light liquid petrolatum, 
with volatile oils. When rubbed on the skin it dilates the 
vessels as camphor does, but it stimulates the "cold" nerves, 
and there is a sensation of numbness of partial anesthesia due 
to a paralysis of the sensory nerves, after primary stimula- 
tion. For this reason it is sometimes used with benefit in neural- 
gias. It is excreted in combination with glycuronic acid as 
menthol-glycuronic acid. 

CH3 . C0.3 CH3 

I I I 

c c c 

/v /\ y\ 

HC CH HC C C CH 

II I II I I II 

HC COH HC COI IOC CH 

\f \/ V 

c c c 

I I I 

C3H7 C3H7 C3H7 

Thymol Dithymol-diiodide (Thymolis iodidum) . 

1. Note odor and test solubility in water, alcohol, ether and 
in fixed oils, of camphor, menthol or thymol. 

2. Triturate a small piece of camphor with thymol, chloral, 
or menthol. 

3. Repeat this with any of the stearoptenes and phenacetin, 
acetanilid or antipyrin. 



180 CHEMICAL PHARMACOLOGY 

Carvacrol is an isomer of thymol. It has the formula 

CH 3 



\OH 



CH 



CH3 CH3 
Carvacrol. 

It occurs with thymol in many labiate plants, particularly in 
the species origanum and in the oil of thyme it sometimes re- 
places all of the thymol. It has the same pharmacological ac- 
tions as thymol and can be used instead of it in hookworm disease. 
Because of the great demand for thymol in the treatment of 
hookworm disease its supply is inadequate. Attempts to produce 
thymol synthetically have not been successful from a commercial 
standpoint. Carvacrol was first prepared synthetically by Sch- 
weitzer (J. Prakt. Chem., 1841, XXIV, 257) and recent work 
shows that it may be prepared synthetically from the commercial 
point of view. (Hixon and McKee, Journal of Industrial and 
Engineering Chemistry, 1918, X, 982). 

Besides its use in the treatment of hookworm disease — thymol 
is occasionally used as a parasiticide. It has been used in ring- 
worm with good results. 5 to 10 per cent, solution in alcohol 
being applied directly to the growth. Thymol is excreted com- 
bined with glycuronic and sulphuric acids. 

XX. RESINS, OLEORESINS, GUM RESINS, AND BALSAMS 

Resins are an ill-defined group of amorphous, brittle oxidized 
hydrocarbons. They are not pure chemical bodies, but mix- 
tures. They are allied to, and probably derived from the vola- 
tile oils, and occur as exudations of plants excreted in the course 



OLEORESINS 181 

of metabolism. Most natural resins consist of a mixture of 
peculiar resin acids, which dissolve in alkalies forming resin 
soaps. These soaps have detergent properties similar to the 
ordinary soaps, and because of their great water-holding power 
have been used to adulterate ordinary soaps. The saponifi- 
cation value aids in the identification of resins. 

Resins are characterized by being insoluble in water and pe- 
troleum ether, soluble in alcohol and volatile oils, and when broken 
by presenting a smooth shining surface, are amorphous, sticky 
and fusible and burn with a smoky flame. They are* almost 
invariably a mixture of different substances. When resins occur 
with volatile oils, N they are called oleoresins. When mixed with 
gums they are gum resins. Balsams are resins or oleoresins that 
contain benzoic or cinnamic acids. The term resin is also used 
in chemistry to include such bodies as are formed when a mixture 
of alcohol and potassium hydrate are allowed to stand. The 
dark colored material that forms and is soluble in the alcohol is 
designated as a resin. 

The most important resins are those of copaiba, jalap, podo- 
phyllum, scammony, guaiacum-wood, gamboge, asafcetida, and 
caoutchouc. Amber is a fossil resin and consists of two resin 
acids, and a volatile oil. Caoutchouc is prepared from a number 
of tropical euphorbiacese, apocinacese, etc. When purified its 
formula is (C 5 H 8 )n. On distillation it will polymerize spontan- 
eously to caoutchouc and also to dipentene. It takes up sul- 
phur readily when treated with sulphur chloride (S 2 C1 2 ) in CS 2 
and the product is vulcanized rubber. 

... — — -4- + 

1. Test the solubility of resin in water, alcohol; ether, oil of 
turpentine, dilute boiling NaOH and H 2 S0 4 . 

2. Mix an alcoholic solution of shellac with water; with dilute 
alcohol. 

3. Mix an alcoholic solution of shellac or resin with mucilage 
of acacia. Shake and let stand. 

OLEORESINS 

These are solutions of resins in ethereal oils. The chief oleo- 
resins are aspidium, eapsicum, cubeb, lupulin, ginger, and black 
pepper. Aspidium is the most important of the group, and is 
used in the treatment of tapeworm. It is the principal remedy for 
this purpose. 



182 CHEMICAL PHARMACOLOGY 

Acetone is the solvent used in the preparation of the oleoresins. 
It is less expensive and less explosive than ether, and is an ex- 
cellent solvent. 

1. Evaporate an alcoholic solution of gum turpentine in a 
small porcelain dish. Note the odor, and the characteristic 
residue. Explain. - -*■'' 

2. Compare the appearance of the oleoresins and the resins. 
To what is the physical difference due?. 1 

3. Place about 25 grams of ginger, pepper, or powdered as- 
pidium in a Soxhlet apparatus and extract with acetone. When 
the extraction is complete distil off the solvent and examine the 
residue-oleoresin. Study the solubility in cotton-seed oil, muci- 
lage and water. Shake. 

GUM RESINS 

Gum resins are mixtures of resins or oleoresins with gums. 
Asafcetida, ammoniac, myrrh, gamboge and scammony are the 
most important. 

Triturate a lump of asafcetida in a mortar with water. Note 
the odor and the character of the mixture. Test the influence of 
the addition of alcohol. This drug is used in neurasthenic 'and 
hysterical conditions. The influence of it, if it has any, is due to 
the odor, i.e. psychic effect. 

Boil some of the gum resin with a little H 2 S0 4 . Neutralize and 
filter. Test the filtrate with Fehling's solution/ Place 5 grams 
of gum in a distilling flask, add 25 cc. concentrated HC1 and distil 
from a sand bath. Let the distillate drop on a piece of filter paper 
moistened with aniline acetate. A red color indicates the pres- 
ence of a pentose, which is converted into furfural by the following 
reaction. 

C 5 H 10 O5 - 3H 2 -> C4H3O.CHO 
Sugar indicates the presence of a gum. Explain the presence and 
kind of sugar. j63A*#^*u-~#fc 

BALSAMS 

Balsams are resins or oleoresins that contain benzoic or cinna- 
mic acid. The most important arc those of peru, tolu , and storax 
or sty rax. Balsam of copaiba contains neither benzoic or cin- 
namic acid and is, therefore, not a balsam. On the other hand 
cranberries and other berries of the Ericaceae, contain benzoic 
acid but contain no resin. 






GLUCOSIDES 183 

XXI. GLUCOSIDES OR COMPOUND SUGARS 

Glucosides are substances which on hydrolysis yield glucose 
or a related sugar, and another substance. In many cases the 
composition of the other substance is unknown; usually it is an 
aromatic body. The sugar may be rhamnose, galactose, ribose, 
arabinose, or any disaccharide that yields a sugar related to glu- 
cose. Some glucosides contain only C, H, and 0, a few have N, 
in addition, and one or two contain sulphur. The part remaining 
after the sugar is split off may be alkaloid, e.g. solanine, in which 
case the term alkaloidal glucoside would be appropriate. Vege- 
table bases however are rarely found in glucosidic combination. 
Some of the glucosides are highly toxic, others inert. The 
characteristic feature is the yield of glucose or related sugar and 
another substance which is not a carbohydrate (different from 
gums, starches, sugars polyoses). They are incompatible with 
free acids, or ferments, since they are decomposed by these agents. 
Some are also decomposed by alkalies. Many have ferments 
associated with them in the plant, which are liberated on crush- 
ing, and in a water solution hydrolyse the glucoside. 

PENTOSIDES, GALACTOSIDES, ETC. 

Some writers restrict the term glucoside to compounds yielding 
hexose sugars, and designate those yielding pentose sugars, as 
pentosides,while those that give galactose on hydrolysis are galac- 
tosides. This is a refinement in classification that may or may 
not be advisable. Pentosanes, hexosanes, etc. differ from pento- 
sides and glucosides in being polyoses and not compounds. On 
hydrolysis pentosanes give pentoses only, hexosanes such as cel- 
lulose give hexoses only. Other writers taking a wider view 
include under glucosides, such polyoses as saccharose, raffinose, 
and gentianose. This is because their combination is ether-like 
and, similar chemically to artificial glucosides. 

CONSTITUTION OF THE GLUCOSIDES 

Chemically, glucosides are ether-like combinations of glucose 
with alcohols, acids, phenols, etc. (see table of composition) . Their 
constitution is analogous in some respects to acetals or aldehyde 
alcohols : 



184 



CHEMICAL PHARMACOLOGY 



H 



OCH; 



R.— C =■ O I OCH 3 -> 

Aldehyde Alcohol 

H 

I /OCH 3 
R.— C( 

X OCH 3 
Acetal. 

Since they contain no free aldehyde groups they will not form 
osazones and will not reduce Fehling's solution until hydrolysed. 

Some glucosides have been prepared synthetically, and* the 
composition of the synthetic product, gives one an idea of gluco- 
sidic composition in general. The best known synthetic glucoside 
is the combination of methyl alcohol and glucose. This is pre- 
pared by treating a concentrated solution of d. glucose in methyl 
alcohol with gaseous hydrochloric acid. Two isomeric products 
are formed. (1) An alpha, glucoside which is dextro-rotatory 
+ 157° and dissolves in 200 parts of alcohol and melts at 165°, 
and beta, glucoside which is levo-rotatory — 33° and is soluble in 
67 parts of alcohol and melts at 104°C. They can be separated 
by their different solubilities. 

The formulas assigned to these different glucosides are: 



(*) 

(7) 

(b) 
(a) 





— C— OCH3 
a-glucoside 



CH3O— C H 

0-glucosidc 



GLUCOSIDES 185 

The a, and Q glucosides are formed simultaneously, the a, 
predominating. Equilibrium is established when the mixture 
contains about 77 per cent, a, and about 23 per cent, of the 6 
isomeride. On standing the /3 form is slowly converted into 
the more stable (a) form. 

The basis for the assumption of these formulas are : 

(I) A single molecule of alcohol reacts with a single mole- 
cule of glucose, with the elimination a molecule of water. One of 
the secondary alcoholic radicals of the sugar must therefore be 
involved. 

(II) These glucosides are readily hydrolysed into their con- 
stituents. This indicates that the alcohol radical is joined to 
the sugar, by means of the oxygen, since if the union were by 
means of the carbon atoms direct, they would not be so easily 
hydrolysed. (Compare the action and fate of alcohol and ether 
in the body.) 

(III) The elimination of water is from the (a, and 7) positions, 
since other compounds containing R — CHOH.CO. do not yield 
glucosides. The (a) group does not react therefore, and in favor 
of the (7) position is the fact that other such combinations are 
known; and only combinations containing the (7) group form 
glucosides. 

From the above, it is seen that there are at least two classes of 
glucosides, the alpha and the beta. Maltase splits or hydrolyses 
the a group, while emulsin hydrolyses the fi group. 

Burquelot's biological method of investigating plants for glu- 
cosides, consists in determining the optical rotation and cupric 
reducing power of extracts before and after incubation with 
emulsin. A change in these properties indicates the presence 
of j8 glucosides, and gives a rough estimate of the amount. 

The following table illustrates the hydrolysing action of these 
enzymes on the different sugars and glucosides. 



186 



CHEMICAL PHARMACOLOGY 



I. 


II. 




III. 


Invertin 


Maltase 


Emulsin 


Saccharose 


Maltose 


Aesculin 


Rafhnose 
Gentianose 


Methyl-d-glucoside-a Amygdalin 
Ethyl-d-glucoside-a Androsin 
Benzyl glucoside Arbutin 
Glycerine glucoside-a Aucubin 
Amygdalin Benzyl-glucoside 
Trehalose Coniferin 




Methyl-d-fructoside Daphnin 
Dhurrin 






Gentiopicrin 
Glyceryl-glucoside 






synigrin 
Helicin 






Incaratrin 






Indican 






Lactose 






Melatin 






Methyl-d-galactoside 8 
Methyl-d-glucoside 6. 
Oleuropein 
Picein 






Prunasin 






Prulaurasin 




CH 2 OH 

1 






1 
H— C— OH 

I 




(7) 


H— C— H 






w 


HO— C— H 






(a) 


H— C— OH 








c =|o " 


+ H 


OCH3 




Methyl a 
H 


lcohol 




Glucose 








187 



+ H 2 



H 

Glucoside 
By treatment with methyl-iodide and silver oxide under proper 
conditions, alpha, and beta pentamethyl glucosides may be pre- 
pared with the formula : 

Me.OC— H 




CH 2 OMe 

(a) pentamethyl glucoside. 
These esters are not acted on by enzymes, but when they are 
hydrolysed by acids, alpha and beta, tetra-methyl glucosides 
are formed: 

HO— (V-H 




188 



CHEMICAL PHARMACOLOGY 



These rapidly change into the same form with constant rotatory 
power. The alpha tetra methyl glucoside is not fermentable, 
but the beta form can be hydrolysed by emulsin. This enzyme 
is especially wide in its action and so far as is known acts only 
on beta glucosides. 

COMPOSITION OF NATURAL GLUCOSIDES 

The natural glucosides are generally colorless crystalline solids 
with bitter taste, and levo-rotatory optical power. All natural 
glucosides so far isolated are of the beta form. They can all 
be hydrolysed by acids though some are very resistant. Emulsin 
will hydrolyse a large number of them. Van Rijn (Die Glu- 
coside) classifies glucosides according to the plants from which 
they are derived. A complete chemical classification cannot be 
given, but according to the non-sugar products of hydrolysis, 
Armstrong (The simple Carbohydrates and Glucosides) gives 
the following table : 



Glucosides 




M.p. 


Products of hydrolysis 


Arbutin 

Baptisin 

Glycyphyllin 

Hesperidin 


Ci2Hi 6 7 
C2CH32O14 
C21H24O9 
C50HC0O27 

C24H260l3 
C13H18O7 

C21H24O1O 

C16H22O8 
C20H22O8 
C13H18O7 
C17H24O9 

C20H27O11N 
O14H17O7N 
C13H1CO7 

CiolInOeN 
C14H17O0N 
CuHwOeN 


187° 
240° 
175° 
251° 
208° 
175° 
170° 
170° 

185° 
180° 
201° 
191° 

200° 

141° 
122° 
147° 
195° 
151° 
160° 


Phenols 
Glucose + hydroquinone 
Rhamnose + baptigenin 
Rhamnose + phloretin 
Rhamnose + 2 glucose + hesperetin 


Methyl arbutin 


Glucose + hydroquinone methyl ether 








Alcohols 












Glucose + syringenin 




Aldehydes 














Prulaurasin 


Glucose + racemic mandclonitrile 
Glucose -f d-mandelonitrile 


Salinigrin 

Sambunigrin 


CuIIieO? 
CuHnOeN 

C19H211O10N 


Glucose + m-oxybcnzaldehyde 

Glucose -+ 1-mandelonitrile 

Glucose -f arabinose + d-mandelonitrile 







GLUCOSIDES 



189 



Glucoside 




M.p. 


Products "of hydrolysis 








Acids 


Convolvulin 


C54H96O27 


150° 


Glucose + rhodeose + convolvulinolic 
acid 




CuHisOa 


100° 






C44H56O16 


131° 




Strophanthin 


C40H66O19 




Rhamnose + mannose + strophantidin 






- 


Oxycumarin Derivatives 




C15H16O9 


205° 








200° 


Glucose + daphnetin 




CisHisOio 


320° 






218° 


3 Glucose + scopoletin 




CisHioOs 


210° 








Oxyanthraquinone derivatives 






228° 








202° 




Ruberythric acid. . . 


C26H28O14 


258° 


Glucose + alizarin 

Oxyflavone derivatives 




C26H28O14 


228° 


Apiose + apigenin 
Rhamnose + fisetin 


Fustin 


C36H26O14 


218° 


Gossypitrin 


C21H20O13 




Glucose + gossypetin 


Incarnatrin . . 


C21H20O12 


242° 


Glucose-quercetin 


Isoquercitrin 


C21H20O12 


217° 


Glucose + quercetin 




C28H31O16N 




2 Glucose + HCN + lotoflavin 


Quercimeritrin 


C21H20O12 


247° 


Glucose + quercetin 






183° 


Rhamnose + quercetin 

Glucose + rhamnose + quercetin 

Glucose + quercetin 

Rhamnose + glucose + sophoretin 

2 Rhamnose + galactose + rhamnetin 






184° 




C21H20O12 


245° 








Xanthorhammin . . . 


C34H42O2O 










Mustard oils 


Glucropaolin 


C14H18O9NS2K 




Glucose + benzyl isothiocyanate 




C30H42O15N2 S2 


138° 


Glucose + sinapin acid sulphate + acrinyl 
isothiocyanate 










C10H16O9NS2K 


126° 


Glucose + allyl + isothiocyanate + 
KHSO4 














Various 


Aucubin 


CnHigOs 




Glucose + aucubigenin 


Barbaloin 


C20H18O9 




d-arabinose + aloemodin 


Calmatambin 


C19H28O13 


144° 


Glucose + calmatambetin 






190° 








217° 


Glucose + digitalose + digitaligenin 
2 Digitoxose + digitoxigenin 
Glucose + xylose + gentienin 




C34H54OH 


145° 


Gentiin 


C25H28O14 


274° 






225° 


Glucose + galactose + digitogenin 
Glucose + gentiogenin 


Gentiopicrin 


C16H20O9 


191° 


Gynocardin 


C13H19O9N 


162° 


Glucose + HCN + C6H 8 04 




CuHitOsN 


100° 


Glucose + indoxyl 

2 Rhamnose + kampherol 




C27H30O14 


201° 








Quinovose + quinovalic acid 
Glucose + saponaretin 
Glucose + galactose + sapogenins 
d-Ribose + guanine 




CisHhOt 












C10H13O5N5 







190 CHEMICAL PHARMACOLOGY 

An examination of this table will show that there is little rela- 
tion between the known chemistry and pharmacological action. 
As a rule, however, the combination of sugar with another radical 
increases the action of that radical. This is well illustrated in the 
action of chloral, which, when combined with glucose to form 
chloralose, is increased and becomes more like morphine in action. 
Relatively few glucosides however are used in medicine. 

The chief glucosidoclastic enzymes are : 

Enzymes Hydrolyses 

Emulsin . ■ , ." Many natural glucosides 

Synthetical /3-glucosides 

Prunase Prunasin and many other 

natural glucosides 

Amygdalase Amygdalin 

Gaultherase Gaultherin 

Linase Linamarin 

Myrosin Sinigrin and sulphur glucosides 

Rhamnase Xanthorhammin 

Emulsin from almonds, hydrolyses, aesculin, amygdalin, andro- 
sin, arbutin, aucubin, bankankosin, calmatambin, coniferin, 
daphnin, dhurrin, gentiopicrin, helicin, incarnatrin, indican, 
melatin, oleuropein, picein, prulaurasin, prunasin, salicin, sam- 
bungrin, syningin, taxicatin, verbenalin, etc. 

The most important glucosides in medicine are : 



Amygdalin 


Helleborein 


Arbutin 


Jalapin 


iEsculin 


Phloridzin 


Coniferin 


Salicin 


Convallarmarin 


Saponin 


Convallarin 


Strophanthin 


Digitalin 


Scillin 


Digitoxin 


Sinigrin 


Digitophyllin 


Sinalbin 


Digitalein 




Digitonin 




Aloin 








GLYCOSIDES 191 

Glychyrrhizin was formerly included in this group, but it is not 
a glucoside. 

Another classification, of glucosides based on the chemical 
groups found in the above is : 

1. Ethylene derivatives. 

2. Benzene derivatives. 

3. Styrolene derivatives. 

4. Anthracene derivatives. 

The chief representatives of this classification are : 
1. Ethylene Derivatives. — Sinigrin CioHi 6 NS 2 K09 + H 2 is 

the glucoside of black pepper, mustard, horse radish and tropse- 
olum seeds. It is the potassium salt of myronic acid. On 
hydrolysis it gives allyl mustard oil, dextrose, and potassium 
bisulphate 

O— S0 2 — OK 

I 

C— S— CeHnOs + H 2 -> C 6 H 12 6 + C3H5NCS + KHSO4 

N— C3H5 

Sinalbin C 30 H 42 N 2 S 2 Oi5, is the corresponding glucoside found 
in white pepper. On hydrolysis it yields mustard oil, glucose, 
and sinapin sulphate, which is a compound of choline and sina- 
pinic acid and sulphuric acid : 

0— S0 2 OC 16 H 24 5 

I 

C— SCHnOe + H 2 -* 

I 

N— CH 2 .C 6 H 4 .OH C 7 H 7 O.NCS 

Sinalbin Sinalbin mustard oil 

OH 



+ CH ; 



OCH3 0H\ 



(CH 3 ) 3 ^N 
/ 

/ 

Sinapin CH : CH - CO.C 2 H 4 



192 



CHEMICAL PHARMACOLOGY 



Jalapin C34H56O16 is the active principle of scammony, has 
been assigned the formula 



CH- 



CoH; 



:CH.CHOH.(C 10 H 20 )COOH 



Its decompositions are not definitely known. 

Jalapin and Scammonium are identical. This glucoside is 
the active principle of scammony (convolvulus scammonia) 
and Ipomoea orizabensis. It has the empiric formula C34H56O16 
and when boiled with dilute acids yields Jalapinolic acid and 
glucose: 



CH 3x 
C 3 4H 56 16 + H 2 = )CH.CHOH.(C 10 H 20 )COOH 

C 2 H./ 



+ 3CeH.i 2 06 



2. Benzene Derivatives. — Arbutin Ci 2 Hi 6 7 is the glucoside 
found in bearberry (uva ursi). The leaves are used in medicine 
and have a diuretic and antiseptic action. The antiseptic action 
is due to the hydroquinone liberated. 



OH 



H 2 



O.CHhOb 

Arbutin 



OH 



OH 

Hydroquinone 



+ C 6 Hi 2 0( 



Glucose 



The hydroquinone due to its oxidation imparts a dark color 
to the urine. 

Amygdalin is one of the best known glucosides and is found in 
bitter almond. After hydrolysis with dilute acids, or ferments, 
the presence of glucose may be shown with Fehling's solution. 



PHLORIDZIN 193 

Benzaldehyde may be detected by its odor. The presence 
of HCN may be shown by its precipitate with AgN0 3 or by the 
Prussian-blue test. When the almond is ground with water, 
at a temperature below 45°C. the enzyme emulsion contained in 
the almond will hydrolyse the glucoside; 

C 20 H 27 NOn + 2H 2 = 2C 6 H 12 6 + C 6 H 5 C^f + HCN 

X H 
Amygdalin Benzaldehyde. 



The physiological action of the drug is due mainly to~the HCN, 
that is liberated in the intestine. Amygdalin is thought to be 
a derivative of the nitrile of mandelic acid : 



CeH 5 CHv yCi 2 H 2 iOio 
X (X 



Mandelic acid (Phenylglycollic acid) C 6 H 5 CH(OH)COOH may 
be obtained by boiling amygdalin with HC1. It may also be 
prepared from benzaldehyde by treatment with HCN and hydro- 
lysing the resulting hydroxy cyanide : 

C 6 H 5 CHO + HCN = C 6 H 5 CH(OH)CN 
C 6 H 5 CH(OH)CN + 2H 2 = C 6 H 5 CH(OH)COOH + NH 3 

Salicin C13H18O7 is the glucoside of Willow bark. On hydroly- 
sis, it yields glucose and saligenin. 

/OH (1) 
C13H18O7 + H 2 = CeH^ -f- CeHi 2 06 

X CH 2 OH (2) 
Saligenin 

Saligenin is the alcohol corresponding to salicylic acid and on 
oxidation will yield salicylic aldehyde and salicylic acid. 

13 



194 



CHEMICAL PHARMACOLOGY 



1. Styrolene Derivatives. — This group contains phenylen- 
ethylene or styrolene C6H 5 CH:CH. Strophanthin and phlorid- 
zin are the most important representatives. 

Phloridzin C21H24O10.2H2O, is a glucoside prepared from the 
root bark of the apple, pear, plum, cherry, and various other 
members of the rosacese. It is much used in experimental work 
and its most pronounced action is the production of glycosuria, 
with a simultaneous hypoglycemia. It is decomposed by dilute 
acids into a glucose and phloretin : 



C21H04O102H0O 



C15H14O5 + C6Hi 2 0e 
Phloretin Glucose 



Phloretin has the following formula : 
OH 

\C0— CH - 



OH 



OH CH, 



OH 



On decomposition, phloretin yields phloroglucin and phloretinic 
acid: 



OH 



C 15 H 14 05 + H 2 



OH 



+ C 6 H, 



OH 



Phloroglucin 



\ 



.OH (1) 
CH(CH 3 )COOH(4) 

Phloretinic acid 



Stropha?ithin. — Several substances have been described under 
this term. Strophanthinum or amorphous strophanthin is 
prepared from strophanthus hispidus and Kombe. Ouabain 



ANTHRACENES 



195 



from strophanthus gratus, known also as g. strophanthin-crystal- 
line, is considered a purer product than the amorphous forms. 
The formula C30H46O129H2O has been assigned to it. 

Arnand, Kohn, and Kulisch isolated a substance from stro- 
phanthus Kombe, which gave the formula C31H48O12 which on 
hydrolysis yielded strophanthidin C19H28O4 and a mixture of 
sugars. 

4. Anthracene or Anthraquinone Derivatives. — Many of the 
anthracene purgatives principles belong in this group. Emodin 
and chrysophanic acid occur as glucosides or rhamnosides. 
Digitoxin, saponin, and strophanthin may be placed here also, 
as in the previous group but the chemistry of these bodies is so 
indefinite that a final classification cannot be made. 

Chrysophanic acid or dioxy methylanthra-quinon 




and Emodin or trioxy methyl 

anthraquinone 
O 
CH 3 OH 




occur in rhubarb, frangula, senna, aloes, etc. The purgative 
property of these bodies has been attributed to the anthracene 
group, to the ketone or quinone groups, and to various side 
chains. Various synthetic bodies of this class have been prepared 




196 CHEMICAL PHARMACOLOGY 

commencing with aloin. These are not so efficient as purgatives, 
as the natural products, because they are too rapidly hydrolysed 
and absorbed from the intestine. Drugs used for their direct action 
in the intestine should not be rapidly absorbed. It is by reason 
of delayed absorption that opium is more efficient in depressing 
movements of the intestine than morphine. 

SAPONIN OR SAPONINS 

The term saponin was originally restricted to the specific 
substance obtained from the root of saponaria rubra and S. alba. 
The term now includes a series of glucosides of which the empir- 
ical formula alone is known. They correspond to the general 
formula CgH^NgOio, and are found in many plants as saponaria 
officinalis, senega, quillaja, digitalis, sarsaparilla, etc. That 
isolated from saponaria officinalis has the formula C19H30O10. 
On hydrolysis, it yields sapogenin, C 14 H 2 20 2 . Solutions of 
saponins foam and become soap-like on shaking. When injected 
intravenously, they cause laking of the blood. Some are very 
toxic and are classified as sapo toxins. Fish are very sensitive 
to saponins. One part of saponin in 100,000 of water will kill 
fish, but this does not render them unfit for food, since saponin 
in this concentration has no action in the gastro-intestinal tract. 

THE DIGITALIS GLUCOSIDES 

The chemistry of these is not definitely known, and in addition 
to the indefiniteness of the chemistry, the nomenclature is con- 
fusing. The principles isolated are probably only approximately 
pure. Schmiedeberg and Kiliani have done the principal work on 
this subject, but the field has just been touched. 

Digitoxin is the most important glucoside. According to 
Kiliani, it has the empiric formula C34H54O11. On hydrolysis, 
digotoxin yields digitoxose and digitoxigenin. Digitoxose. 

C84H54OH + H 2 = 2C 6 H 12 4 + C 22 H 32 4 

Digitoxose Digitoxigenin 

crystallizes in crystals and plates, M.P. 102°C. and is of dextro- 
rotatory constitution. 



GLUCOSIDES 197 

Digitalin, C35H56O14 or CseHseOn, according to Kiliani hy- 
drolysis into digitalose, digitaligenin, and dextrose : 

C35H56O14 = C6H12O6 + C7H14O5 + C22H30O3 

dextrose digitalose digitaligenin 

Digitonin, C55H94O28 or C54H92O28. This is a saponin, soluble 
in alcohol from which it crystallizes in fine needles m.p. 235°C. 
On hydrolyses : 

C55H94O282H2O = C31H50O6 -f- 2C0H12O6 + 2C6Hi20c 
digitonin digitogenin dextrose galactose 

The commercial digitalins are impure and variable mixtures of 
digitalis principles. 

Convallamarin, C23H44O12, and convallarin, C34H62OU, are 
two glucosides occurring in convallaria majalis (lily-of-the-valley) . 
Convallamarin is soluble in water and alcohol, insoluble in ether 
and chloroform, is an acrid glucoside, soluble in water, sparingly 
soluble in alcohol, and insoluble in ether and is a saponin-like 
glucoside. Little is known of the split products of these glu- 
cosides. 

Digitalein, C22H38O9, was supposed by Schmiedeberg to be a 
pure product but is not now considered a chemical entity. The 
same is true of digit ophyllin. 

Glycyrrhizin, C44H63NO18, is the sweet principle of licorice 
root. It occurs as the ammonium salt of glycyrrhizic acid, 
C4 4 H 6 2(NH.)4N0 1 8, and on hydrolysis it yields glycyrrhetin, 
C32H47NO4, and para saccharic acid, CeHioOs. 

This acid reduces Fehling's solution and for this reason gly- 
cyrrhizin was formerly thought to be a glucoside. 

Scillin, from squill, is a mixture of glucosides, the chemistry 
of which is unknown. 

Helleborin, C36H42O6, is found in black hellebore. On hydroly- 
sis it gives helleboresin, C 3 oH 38 04, and sugar. Helleborein, 
C26H44O15, is another glucoside obtained from the same source. 
On hydrolysis it yields hellebore tin, C14H20O3, and sugar. 



198 CHEMICAL PHARMACOLOGY 

CYANOGENETIC GLUCOSIDES 

The cyanogenetic glucosides yield hydrocyanic acid on hydroly- 
sis. They are of interest chiefly because they are considered 
as the connecting link between the carbohydrates and the alka- 
loids and other nitrogen containing compounds. Their composi- 
tion differs in different plants. Hydrocyanic acid occurs in 
many plants sometimes in the free state but mostly in combina- 
tion. The nature of many of the compounds is unknown. Many 
are in the form of glucosides and it seems that this is the general 
condition of hydrocyanic acid in the plant. However, 
nitrogen may occur in glucosides in other forms. The cyano- 
genetic glucosides occurs chiefly in the buds, seeds, leaves, and 
bark. 

With regard to the formation of hydrocyanic in the plant 
nothing is definitely known. Gautier supposes that it may be 
due to the reduction of nitrates by formaldehyde. 

The chief cyanogenetic glucosides are: 

Amygdalin Dhurrin 

Amygdonitrile (Prunasin) 

Sambunigrin Gynocardin and 

Prulaurasin Vicianin 
Phaseolunatin 
Lotusin 



SOLANIN 

Solanin is an alkaloidal glucoside found in all parts of the 
potato plant. Its composition is not definitely known. In its 
action it resembles the saponins and is a general protoplasm 
poison killing bacteria and hemolyzing red cells in extreme 
dilutions. Its salts are amorphous and gummy. It is not 
affected by alkalies but acids decompose it into solanidin and 
a mixture of sugars including dextrose, rhamnose and galactose. 
It dissolves in nitric acid with a yellow color, slowly changing to 
red. It gives a green tint with sulphuric acid in alcohol and a 
red color with a mixture of sulphuric acid and sodium sulphate. 



INDICAN 



199 



CONIFERIN 

Ci 6 H 2 20 8 . This glucoside occurs in various coniferous trees 
and in asparagus. On hydrolysis with mineral acids or emulsin 
it yields glucose and coniferyl alcohol. 

C16H22O8 -f- H2O — > CeHi206 -f" C10H12O3 

Coniferyl alcohol. 

When coniferyl alcohol is oxidized with potassium bichromate 
and sulphuric acid it yields vanillin. Artificial vanillin was 
formerly prepared by this method. It is now prepared by the 
oxidation of isoeugenol, which in turn is prepared by boiling 
eugenol, the chief constituent of oil of cloves. The relationship 
is shown by the formulas : 

CH = CHCH2OH CHO CH = CHCH 3 



OCH 3 
OH 

Coniferyl alcohol. 



0CH3 \y 0CH3 

OH OH 

Vanillin Iso-eugenol 

CH2.CH '. CH; 



OCH3 

OH 
Eugenol 
INDICAN 

This glucoside occurs in a number of plants, especially indigo 
fera anil, I. sumatrana, and I. arrecta. It is decomposed on 
hydrolysis into indoxyl and glucose as follows: 
CrHeNC.O.CeHnOs^HsO 

/ NH 
C6H4V ^~~^CH + CeHi20c 

x C(OHy 



200 



CHEMICAL PHARMACOLOGY 



Indoxyl 
The dye indigo, is formed from indoxyl by oxidation as follows : 



C— O H H 0— C 



+ 



C H HIC 



NH 



NH 



2 Indoxyl 
CO CO 






NH 



NH 



Indigo blue 



COH HOC 



C\ 



NH 



NH 



Indigo white 
The name indican is also applied to a compound of the 



formula: 



\ 



C— OS0 3 K 



/CH 



NH 



ANIMAL GLUCOSIDES 201 

which occurs in the urine in cases of intestinal putrefaction, and 
is derived from tryptophane, in a manner not yet understood. 
The relationship is shown by the formula: 



y CH \ 

HC C C— CH 2 — CHNH 2 — COOH 



HC C CH 

Tryptophane 

y CH \ y CH \ 

HC C CH HC C— COH 

I II II - I II II 

HC C CH HC C CH 

\m //Nv NEr // ^CH^^NH^ 

Indole Indoxyl 

y CH \ / CH v 

HC C —CO OC— - — C CH 

I II I I II I 

HC C C— C C CH 

Indigo blue 

The indigo blue in this case is the same as derived from glu- 
coside indican. It is now produced synthetically; 



ANIMAL GLUCOSIDES 

Glucoside like combinations are found in the animal organism. 
The importance of these is not well understood. The term glu- 
coside itself it must be remembered is not strictly defined. Thier- 
felder isolated a glucoside like substance from the human brain 



202 CHEMICAL PHARMACOLOGY 

which he called cerebron, a galactoside. On hydrolysis this 
yielded cerebronic acid, sphingosine and galactose: 

C 4 8H 93 N0 9 2H 2 0->C 25 H 5 o03 + 
Cerebron Cerebronic acid. 

C17H35NO2 + C6H12O6 
Sphingosin Galactose. 



Cerebron appears to be a mixture of two glucosidic bodies 
which have been named Phrenosin (Phren. brain) and kerasin. 
Phrenosin yields, sphingosin and galactose kerasin resembles 
phrenosin, the differences being mainly that kerasin contains 
lignoceric acid C24H48O2 instead of cerebronic. The chemistry 
of all these bodies is far from complete. Some of the nucleic 
acids contain pentosides, and perhaps other glucosides occur in 
the brain substance. The importance of these in the animal 
economy for the present cannot be evaluated. That they are 
very important can be readily seen when we consider the im- 
portance of the nucleins to the life of the cell, and the importance 
of the brain tissue in anesthesia, and other drug action, and to 
life generally. 



THE FUNCTIONS,'ACTION, AND FATE OF GLUCOSIDES 

The physiological importance of glucosides is not definitely 
known. They appear again and again in plants under similar 
conditions and it would seem that like the carbohydrates, they are 
associated with the metabolism of the plant. As a rule they are 
found in greatest amount where metabolism is most active as in 
leaves and shoots. Since the time of the maximum amount of 
glucosides in plants varies in different plants, their function in 
the different plants may also vary. They may be of value as 
food stuffs or as reserve food stuffs. Glucosides as a rule are 
hydrolysed readily in the upper part of the alimentary tract. 
In the case of the digitalis glucosides none reach the large bowel 
unchanged. After large doses some of the glucoside has been 
found in the liver but not in other organs. The principles have 
been found in the urine and faeces, so that both kidney and gut 



TESTS FOR GLYCOSIDES 203 

take part in the excretion. The hydrolysed products are active 
ingredients, though the sugar rnoiety increases the action. Just 
how much of the active part is oxidized in the body is unknown. 
The galactoside of the brain is interesting in view of the fact 
that all lecithins of vegetable origin are in glucosidic combination. 
Galactose, glucose, and pectose, have been identified in these 
lecithin glucosides of plants. 

Tests for Glucosides 

1. Test a 1 per cent, solution of salicin or amygdalin with 
Fehling's solution. 

2. Acidify another portion of the glucoside with H 2 S0 4 , boil 
for 5 minutes, make neutral or slightly alkaline with NaOH or 
KOH, and apply Fehling's. 

3. To another portion add some saliva and keep at body tem- 
perature for 15 minutes, then test for sugar. 

4. Pulverize some bitter almonds in a mortar. Note the odor 
of the dry powder. Divide into two parts. Mix one part with 
water at 40°C, and set aside for 15 minutes. Boil the other por- 
tion for 5 minutes by adding the boiling water directly to it, and 
continuing the boiling. Test both solutions for HCN as follows : 
Filter make alkaline with a few drops of KOH, and add a few 
drops of freshly prepared ferrous sulphate solution. After al- 
lowing it to stand for 4 minutes acidify with HC1. A Prussian 
blue color indicates the presence of HCN. See reaction for N 
under alkaloids. Difference between the boiled and the unboiled 
portions? Bitter almonds contain a ferment-emulsin. 

5. To 5 cc. of the fluid extract of licorice, add just enough 
1 per cent. Na2C0 3 to make alkaline. Acidify another 5 cc. 
with H2SO4. Compare the taste of the two solutions. Acids are 
incompatible with glycyrrhiza. 

6. Digitalin: Use only a trace of the dry substance in making 
the tests, (a) The solution in H 2 S0 4 is yellow. This turns 
blood red or violet on adding a drop of HN0 3 or Fe 2 Cl 6 . (b) 
Dissolve a trace of the dry substance in a test tube. Add a 
mere trace of Fe 2 Cl 6 with a glass rod. Add an equal volume 
of cone. H 2 S0 4 without mixing. If digitalin is present 'there 
is a persistent carmine zone at the point of contact, (c) Place 



204 CHEMICAL PHARMACOLOGY 

a small piece of the dry substance on a white plate. Add a 
drop of Fe 2 Cl6 and cone. H2SO4 without mixing. A carmine 
or violet zone which changes to indigo results (Kiliani). (d) 
Physiologic test. This must be taken into consideration with 
the above. The slowing and systolic standstill of the frog's 
heart is characteristic. 

7. To a portion of a glucosidal solution add 2 cc. of saliva. 
Keep it at 40°C. for 15 minutes and test for sugar as in 2. 

8. Guignard's test for cyanogenetic glucosides. Strips of 
filter paper are dipped in 1 per cent, picric acid solution and 
dried; they are now moistened with 10 per cent, solution of 
Na 2 C0 3 and again dried. In the fumes of HCN, these papers 
turn red due to the formation of potassium isopurpurate. If 
these papers be suspended over a solution containing HCN 
they become red gradually. The rate depending on the amount 
of acid present. Hydrogen sulphide gives this same reaction 
due to the formation of picraminic acid, and sugar heated in 
a solution of alkaline picric acid also gives the red color. 



XXII. BITTER PRINCIPLES 

Bitters have nothing in common except their bitter taste, and 
cannot be classified chemically. All distinctly bitter extractives 
other than alkaloids, glucosides, and neutral principles that are 
not toxic, are included under the term bitters. The neutral 
principles differ from the bitters only in their higher activity and 
toxicity. 

Tests to Distinguish Bitters from Other Bodies 

1. They are not precipitated by alkaloidal reagents — different 
from alkaloids. 

2. They do not yield sugar on hydrolysis — different from 
glucosides. 

3. Bitters are physiologically rather inert — different from 
neutral principles and alkaloids. 

Pharmacologic Classification. — Bitters may be conveniently 
placed under four heads: 



BITTERS 205 

I. Simple Bitters. — These are practically free from tannin 
and aromatic oils, and include gentian, quassia, calumba, taraxa- 
cum, chirata, pareira, and calendula. The fluid extract and 
tincture are the most important preparations. 

II. Astringent Bitters.- — These contain tannin, which makes 
them astringent. Serpentaria, cimicifuga, condurango, and 
cascarilla are the chief representatives of this class. 

III. Aromatic Bitters. — These contain more volatile oil than 
the other classes, and less tannin than the astringent group. The 
principal representatives are calamus, aurantii amara cortex, 
anthemis, serpentaria, and prunus virginiana. 

IV. Compound Bitters. — These are mixtures of simple bitters. 
Blending is said to improve their action. Tinctura gentina com- 
posita, elixir aromaticum, tincture amara, and vinum aurantii 
compositum belong to this class. 



XXIII. PHARMACOLOGY OF THE TASTE AND SMELL 

The nerves which mediate taste and smell are the first or 
Olfactory (L. Oleo — smell; facio — to make) and the ninth or 
glossopharyngeal. 

Kant defined smell as taste at a distance, taste and smell being 
related. The olfactory is a nerve of special sensation and hard to 
investigate because its receptive surfaces are intimately associ- 
ated with those of the 5th nerve — a nerve of common sensation. 
For this reason true smells, or those substances which stimulate 
the olfactory only, are hard to separate from pungent substances 
like vinegar which also stimulates the 5th nerve. 

For the correlation of odor and structure we are indebted 
mainly to Georg Cohn (Die Reichstoffe, 1904) and Zwaarde- 
maker (Physiologie des Geruchs, 1895). 

Zwaardemaker separates pure odors into nine classes which 
have been arranged by Howell (Text Book of Physiology) as 
follows : 

1. Odores setherei or ethereal odors, such as are given by 
the fruits, which depend upon the presence of ethereal substances 
or esters. 

2. Odores aromatici or aromatic odors, which are typified by 



206 CHEMICAL PHARMACOLOGY 

camphor and citron, bitter almond and the resinous bodies. 
This class is divided into five subgroups. 

3. Odores fragrantes, the fragrant or balsamic odors, compris- 
ing the various flower odors or perfumes. The class falls into 
three subgroups. 

4. Odores ambrosiaci, the ambrosial odors, typified by amber 
and musk. This odor is present in the flesh, blood, or excrement 
of some animals, being referable in the last instance to the 
bile. 

5. Odores alliacei or garlic odors, such as are found in the 
onion, garlic, sulphur, selenium and tellurium compounds. These 
fall into three subgroups. 

6. Odores empyreumatici or the burning odors, the odors given 
by roasted coffee, baked bread, tobacco smoke, etc. The odors 
of benzene, phenol, and the products of dry distillation of wood 
come under this class. 

7. Odores hircini or goat odors. The odor of this animal arises 
from the caproic and caprylic acid contained in the sweat. 
Cheese, sweat, spermatic and vaginal secretions give odors of 
similar quality. 

8. Odores tetri or repulsive odors, such as are given by many 
of the narcotic plants and acanthus. 

9. Odores nauseosi or nauseating or fetid odors, such as are 
given by feces, by certain plants and the products of putrefaction. 

Beaunis classified all substances which affect the olfactory 
mucous membranes into three groups (Stewart, Text Book of 
Physiology), as follows: 

1. Those which act only on the olfactory nerves: (a) Pure 
scents or perfumes, without pungency. (6) Odors with a certain 
pungency — e.g., menthol. 

2. Substances which act at the same time on olfactory nerves, 
and on nerves of common sensation (tactile nerves) — e.g., acetic 
acid. 

3. Substances which act only on the nerves of common sensa- 
tion (tactile nerves) — e.g. carbon dioxide. 

Haller divided odors into: 

1. Ambrosial or agrecabl<\ 

2. Fetid or disagreeable, . 

3. Mixed. 



CHEMISTRY OF SMELL 207 

And in every day life the division is usually made into : 

1. Pleasant, or agreeable. 

2. Disgusting, or disagreeable. 

CHEMISTRY AND PHYSICS OF ODORS 

It was formerly believed that before a substance is recognized 
as odoriferous, particles must reach the olfactory nerve through 
the air. However, odor may be detected when substances are 
dissolved in saline, or in the pharmaceutic waters, and taken into 
the nostrils. 

The concentration of the substances in the liquid is of some 
importance, since cumarin, vanillin, oil of rose, etc., and other 
substances have different odors in strong and dilute solutions. 

Practically, however, volatility is the most essential condition 
for production of an odor. Since volatilty is mainly dependent 
on molecular weight, chemistry plays an important part. In 
chemical compounds, it has been found that certain groups or 
radicals give rise to rather distinctive odors. These groups are 
called the osmophore groups (osmo — odor; phero — to bear). 

Two or more osmophore groups may occur in the same sub- 
stance. Investigation of these groups has not gone far enough 
to classify odoriferous bodies on their chemical groupings. The 
modifying influence of associated groups is not yet understood. 
Hydroxyl, aldehyde, ketone, nitrile, nitro and azoimide groups 
are all osmophoric, but may produce pleasant or unpleasant 
odors, and prediction as to the result is very uncertain. How- 
ever, certain facts are established: 

1. Homologous derivatives usually have a similar odor. 

2. Phenols have characteristic odors. 

3. The odor of alcohols is usually pleasant. 

4. Unsaturated substances, which are usually chemically 
reactive, generally have powerful odors. Triple linked com- 
pounds are usually unpleasant. 

5. If an aldehyde has a pleasant odor, reduction alters the 
odor, but does not make it disagreeable. 

Drugs that act centrally may stimulate or depress the sensation 
of the olfactory nerve; strychnine and caffeine stimulate it, 
while chloral depresses. Cocaine applied to the nasal mucous 



208 • CHEMICAL PHARMACOLOGY 

membranes paralyzes the sensation of smell entirely. Marked 
changes in the nerve may occur in disease and the sensation of 
smell may be entirely abolished (anosmia). Overstimulation 
because of the fatigue produced, may also cause this. 

Fatigue of the nerve is quite common. Odors soon give no 
sensation when the stimulation is continued, and unpleasant odors, 
coal gas, etc., by continued action soon lose their effect. 

TASTE 

Before a substance can stimulate the taste nerves it must be 
soluble in the fluids of the mouth. Accordingly as they affect 
the taste, sapid substances have been classified as follows: 

1. Sweet 

2. Bitter 

3. Acid 

4. Saline 

Regarding the mechanism by which sapid substances stimu- 
late the gustatory nerve endings we know but little, but the 
stimulus acts on the end organs and not on the nerve trunks. 
Nerve trunks in general are not stimulated by any pharma- 
cological agent, unless it be applied directly to them; but a sen- 
sation of taste is not developed by direct application to the nerve 
trunk. Attempts have been made to find a chemical group 
responsible for taste, but little progress has yet been made. 
Acids and bases owe their characteristic taste to the H, and alka- 
lies to the OH ions. 

Sternberg ascribes the bitter taste of alkaloids to their cyclic 
constitution,, but this assertion will not bear analysis. In the 
Mendeljef periodic classification of the elements, the sweet 
tasting elements boron, aluminum, scandium, yttrium, lanthanum 
are found in the third groups, while lead and cerium are in the 
fourth. Beryllium, another sweet tasting element, is in the 
second, while chlorine which often gives rise to sweet compounds 
is in the seventh. 

The bitter elements — magnesium, zinc, cadmium and mercury 
— are found in the second. Sulphur in the sixth group often 
gives rise fco bitter compounds. 



TASTE 209 

The hydroxyl group has often been associated with a sweet 
taste. Sternberg (Geschmack and Geruch) has pointed out that 
in organic compounds, in order to have a sweet taste the alkyl 
groups must not exceed the OH groups, by more than one, or 
their combination will be bitter. 

Thus Rhamnose: CH 3 (CHOH) 4 CHO is sweet, 
CH 3 

(CHOH) 3 
but methyl rhamnoside CH\ is bitter. 

I > 

I 

OCH 3 

Again, the sweetness in an homologous series increases with the 

CH 2 OH 
increase of hydroxyl groups, e.g. glycol: I 

CH2OH 

CH2OH 

I 
is sweet, but not so sweet as glycerol: CHOH 

-\ 
CH 2 OH 

and glucose: 

CH 2 OH 
(CHOH) 4 
CHO 

is still sweeter. Most substances with the formula (CH 2 0)n 
are sweet. That other factors than the OH groups enter into 
the production of a sweet taste is shown by the fact that lead 
acetate is sweet, yet contains no OH groups; and saccharin, 
five hundred times sweeter than cane sugar, contains no OH 
groups. Again the corresponding para compound of saccharin 
is tastelesss, showing that the architecture of the molecule is 
perhaps more important than the chemical grouping. It has been 
suggested that the stimulation of the taste buds is a physical 
process due to intramolecular vibrations, but we have no way of 
testing such a suggestion. 

Again in those aromatic bodies containing an OH group the 
position of this in the ring and the relation to other groups is 
interesting, e.g. : 

14 



210 



OH 



OH 



CHEMICAL PHARMACOLOGY 

OH OH 

/\ 

OH 



OH 



OH 



OH OH 



OH 



Pyrocatechol Resorcinol 
(bitter) (sweet) 



NH- 



Pyrogallol 
(bitter) 



COOH 



Anthranilic acid 
(sweet) 
OC 2 H 5 



NH.CO.NH 2 
Para phenetol or 
Dulcin (sweet) 



/ \so s 



:NH 



CO' 



Saccharin 
(very sweet) 



Phloroglucinol 

(sweet) 



S0 2 . 

^NH 
CO/ j 



NH 2 

Amino saccharin 

■ (very' sweet) 



S0 2 



\ 



NH 



CO 



Br 
Brom saccharin 
(first sweet, 
then bitter) 






CO, 



CO' 



NH 



SO, 



CO 



:NH 



Phthalimide — very similar in com- 
position to saccharin — is not 

sweet. 



N0 2 
Nitro saccharin^ 
(very bitter) 



CHEMISTRY OF TASTE 211 

This shows that the arrangement of the molecule is of consider- 
able importance, but we cannot explain taste in relation to struc- 
ture. Saccharin is an ortho compound; resorcin a meta; and 
dulcin a paracompound, all of which are sweet. This is further 
illustrated by the differences in the taste of optical isomers; 
dextro-asparagin is sweet while levo-asparagin is not; and dextro- 
glutaminic acid is sweet, whereas the levo acid is tasteless. 

In a recent study of the chemistry of taste, Oertly and Meyers 
(Journal of Am. Chem. Society, 1919, vol. 41, p. 855) have worked 
out a theory relating to the aliphatic sweet stuffs. They think 
that taste is dependent on two factors, or chemical groups, — a 
glucophoric and an auxogluc. They define a glucophore as a 
group of atoms which has the power to form sweet compounds 
by uniting with a number of otherwise tasteless atoms or radicals. 
An auxogluc is defined as an atom or radical which combined with 
any of the glucophores yields a sweet compound. Any gluco- 
phore will form a sweet compound with any auxogluc. 

The following radicals are found to be glucophores in the sense 
of their theory: 

1. -CO— CHOH(+ H), 4. CHoOH.CHOH- 

2. C0 2 H.CHNH 2 -. 5. CH 2 ON0 2 - 

3. H 3 -x 6. H 3 -x H 2 -y 
C — C — C — 

HI, HI, Hl y 

The (-j- H) in glucophore 1, simply indicates that the group 
must be united with one hydrogen atom at least, in order to 
become a glucophore. 

In the general formula H 3 -x the abbreviation HI is general 

C — 
HI, 
for chlorine, bromine, and iodine. Flourine derivatives may be 
included possibly. The small index (x) refers to the number of 
halogen atoms in the glucophore. It may vary from one to three, 
the number of hydrogen atoms in the glucophore meanwhile 
decreasing from two to zero; e.g., methyl iodide has the 
glucophore CH 2 I — . In this case I limits the abbreviation 
HI to a single atom of halogen. The index (x) equals one. 



212 CHEMICAL PHAKMACOLOGY 

In respect to the hydrogen, the index is 3 — x which is equal 
to two, hence CH 2 I — agrees with the general formula. Chloro- 
form has the glucophore — CC1 3 which also agrees with the 
general formula. The index (y) has the same significance as 
(x) but varies from one to two. 

The following atoms or radicals seem to act as auxo- 
glucs, yielding with glucophores sweet compounds : 

(a) H, hydrogen. 

(6) The radicals, C n H 2n +iO, of saturated hydrocarbons, con- 
taining from 1 to 3 carbon atoms. Example CH 3 CH 2 — 

(c) The radicals C n H 2n +iO of monohydric alcohols, n being 
equal to one or two. Example CH 2 OH — 

(d) The radicals C n H 2 n-iO n of polyhydric alcohols. Example 
CH 2 OH.CHOH— 

The following tables indicate more clearly the significance of 
glucophores and auxoglucs. 

Table I.— Glucophore CH 2 OH— CHOH— - 

Auxogluc Name of Compound Taste 

H— Glycol Sweet 

CH 3 — 1, 2-Propanediol Sweetish 

CH 3 CH 2 — 1, 2-Butanediol Sweetish 

CH 2 OH— Glycerol Sweet 

C n H 2 n-i Polyhydric alcohols All sweet 

Table II.— Glucophore, — CO.CHOH— H. 

H — Glycollic aldehyde Distinctly sweet 

CH 3 — Oxy acetone Sweet 

CH 2 OH — Glyceric aldehyde Sweet and bitter 

monomolecular Slightly sweet 

bimolecular Sweet 

Dioxyacetone Sweet 
CH 3 CHOH — .. Methyl-glyceric 

aldehyde, 

CH 3 (CHOH) 2 CHO Sweet and bitter 

Methyl-dioxyacetone Sweetish 

C»H2n-iOn .... Sugars, e,g. hexoses Sweet 



GLUC0PH0RES 



213 



Table III— Gltjcophore, C0 2 H— CHNH 2 

Auxogluc Name Taste 

H — Amino-acetic acid Sweet 

CH 3 — dl-a- Amino-propionic acid Sweet 

CH3CH2 — dl-a-Amino-butyric acid Sweet 

CH 3 (CH 2 )2 — dl-a-Amino-n-valeric acid Sweet 

CH2OH — dl-Serine, a-amino-/3-hy- 

droxy propionic acid Sweet 
CH 3 CHOH— . dl-a-Amino-j(3-hydroxy-bu- 

tyric acid Sweet 

C n H 2 n-iOn — • • d-Glucosaminic acid Agreeably sweet 



Table IV.— Glxjcophore CH 2 ON0 2 — 

Sweet 

Sweet 

Sweet 

Sweetish 

Sweet 



CH 3 _ Ethyl nitrate 

CH 3 (CH 2 ) 2re — . . Butyl nitrate 

(CH 3 ) 2 CH— . . Isobutyl nitrate 

(CH 3 ) 2 CHCH 2 _ Isoamyl nitrate 

CH 2 OH — '. Glycol mononitrate 



H 3 _a; 

Table V. — Glucophore C 

HI, 

H — Methyl chloride Sweetish 

Methylene chloride Sweetish 

Chloroform Sweet 

Bromoform Sweetish 

Iodoform Sweetish 

CH 3 . Ethyl chloride Sweetish 

Ethyl bromide Burning 

CH 2 OH — Ethylene chloro hydrine Sweet 



214 



CHEMICAL PHARMACOLOGY 





H3-3 N2-S 


Table VI — Gltjcophore 


C — C 




HU Hl y 


. Ethylene chloride 


Sweetish 


Ethylene bromide 


Sweetish 


Ethylene chloro-iodide 


Sweet 


. 2-Chloro-i-iodopropane 


Sweet 


. 2, 3-Dichloro-i-hydroxy- 




propane 


Burning spicy 



H— 

CH 3 — 

CH2OH— .. 

2, Chloro-3-bromo- 
propanei-ol 



Sweet 



XXIV. TANNIC, DIGALLIC ACID, OR GALLOTANIC ACID 



C14H10O29, or 
CO— 



-0 



HO 



OH HOOC 



OH 

occurs in large quantities 

OH 



OH 



in gall nuts and in all kinds of bark, especially oak. It is the ac- 
tive constituent of all vegetable astringents. Its pharmacologic 
action is the same as that of metallic astringents and is due to a 
union with, and precipitation of, proteins. Tannic acid is soluble 
in water, alcohol, or ether. When boiled with H 2 S0 4 it is com- 
pletely converted into two molecules of gallic acid which shows 
that it is a gallic acid anhydride, 

OH 

OH 
C 14 H 10 Ofl+ H 2 ->2 

ohv. yc 

Gallic acid 



TANNINS 215 

though it is not known which OH group unites with the carboxyl 
in the synthesis. All tannins, tannic acid, and gallic acid are 
reducing agents, and because of this it was formerly thought 
that they were all glucosides. It is now known that not all of 
them are e.g. pure tannic acid. Ordinary tannin, is impure tannic 
acid and on hydrolysis yields 7-8 per cent, of glucose. The com- 
position varies, in some, tannins having been found to be the 
penta digallic ester of glucose. 

CH 2 — t 

CHO— t 

I 
CH 

I 
/CHO — t "t" represents tannic acid. 

oS CHO— t 

^CHO 

The composition of many tannins has not been determined. 

Tannic acid unites with albumin and is an alkaloidal reagent, 
while gallic acid is not. Animal skins properly treated with it 
are tanned. Tinctures were formerly detannated by shaking 
with finely ground animal hides, but this method has been 
given up. Tannin forms inks with iron salts, and for this rea- 
son, tannins and iron salts are incompatible. According to 
the color of the ink so formed, tannins have been divided into 
two classes, first — the pyrogallol class, which gives a dark blue 
color, and second — the catechol class which gives a greenish 
color. 

Tannins differ in the tendency to unite with proteins. A de- 
coction of tea is a much more efficient precipitant than a similar 
decoction of coffee. 



216 CHEMICAL PHARMACOLOGY 

On heating gallic acid C0 2 is given off and pyrogallol 
formed. — 



OH 


OH 

A 




OH 


OH 


OH 

C 


Gallic aci< 


COOH 

i ] 


iVrogallo 


OH 

1 



+ CO 



All tannins absorb oxygen readily, but pyrogallol does so to a 
much greater extent. 

Tannic acid is used in medicine for its astringent properties : 
externally in cases of local sweating or weeping ulcers, and to 
harden the skin. Lead, zinc, and alum salts are used for the same 
purpose. In inflammations of the throat, it is used in lozenge 
form as an astringent. In cases of diarrhcea it is used in the form 
of tinctures of Kino, Krameria, Gambir, Catechu, etc. Its ac- 
tion in these cases is due to a combination with the material in 
the gut and also to a similar action on the gut wall, which it 
protects. It is used as an antidote in cases of poisoning with 
alkaloids and heavy metals with which it combines. In such 
cases the precipitated material must be removed or the combina- 
tion is digested in the body and the action of the alkaloid is 
only delayed and not avoided. This delay however may pre- 
vent an action by the drug, since such delay may enable the body 
to oxidize or excrete it as fast as it is absorbed. In some indi- 
viduals, with an idiosyncrasy, tannic acid induces local irritation 
and inflammation. . 

FATE IN THE BODY 

When tannic acid is taken internally most of it, in some cases 
all, is oxidized. Traces may be excreted in the urine, and feces. 
It does not exist in the tissues as such but as the gallate or tannate 
of sodium. These are devoid of astringent effects. According 
to Harnack, pyrogallol is sometimes formed from gallic acid in 
the urine. 



TANNINS 217 

Tests for Tannin 

1. Test the solubility of tannic acid in water, alcohol, ether, 
chloroform. Repeat with gallic acid. 

2. Add a solution of ferric chloride to tannic acid. Lead ace- 
tate added to tannic acid produces a white precipitate; if NaOH 
is added to this and the mixture shaken, a pink color is formed. 

3. Add tannic acid to a solution of albumin (a) excess albumin; 
(b) excess tannic acid; (c) potassium hydroxide. Repeat with 
gallic acid. 

4. Neutralize a solution of tannic acid with KOH solution. 
Add to this neutral solution albumin and compare the result with 
that obtained in 3. 

5. Add tannic acid to a solution of 1 per cent, quinine bisul- 
phate. Repeat with 0.1 per cent, strychnine sulphate. 

6. To a 1 per cent, solution of gallic acid add a few drops of 1 
per cent. KCN, and there will appear a red color which soon 
fades but reappears on shaking (Young's test). Pure tannic 
acid does not give this reaction. 

7. Boil 1 gm. tannin 15 minutes with 10 cc. of 5 per cent. H 2 S0 4 . 
Neutralize and apply Fehling's test. What is the result? 
Meaning? 

8. Permanganate solutions oxidize tannic acid. To 5 cc. 
tannic acid solution add drop by drop KMn0 4 and note 
results. This fact is used in the quantitative determination of 
tannin. This is illustrated in the following method — Procter's 
Modification of Lowenthals — for the determination of tannin in 
tea. 

(A) Preparation of Reagents 

1. Potassium permanganate. Make up a solution containing 
1.33 grams per liter. 

2. Tenth-normal oxalic acid. Make up a solution containing 
6.3 grams per liter. 

3. Indigo carmine. Make up a solution containing 6 grams 
of indigo carmine (free from indigo blue) and 50 cc. of concentrated 
sulphuric acid per liter. 

4. Gelatin solution. Prepare by soaking 25 grams of gelatin 
for one hour in a saturated sodium chloride solution, heat until 
the gelatin is dissolved, and make up to 1 liter after cooling. 



218 CHEMICAL PHARMACOLOGY 

5. Mixture. Combine 975 cc. of saturated sodium chloride 
solution and 25 cc. of concentrated sulphuric acid. 

6. Powdered kaolin. 

(B) Determination 

Obtain the value of the potassium permanganate in terms of 
the oxalic acid. Boil 5 grams of the tea for half an hour with 400 
cc. of water; cool, transfer to a graduated 500 cc. flask, and make 
up to the mark. To 10 cc. of the infusion (filtered if not clear) 
add 25 cc. of the indigo carmine solution and about 750 cc. of 
water. Add from a burette the potassium permanganate solu- 
tion, a little at a time while stirring, until the color becomes light 
green, then cautiously, drop by drop, until the color changes to 
bright yellow or, further, to a faint pink at the rim. The number 
of cubic centimeters of permanganate used furnishes the value 
(a) of the formula given below. 

Mix 100 cc. of the clear infusion of tea with 50 cc. of gelatin 
solution, 100 cc. of salt acid solution, and 10 grams of kaolin, 
and shake several minutes in a corked flask. After settling 
decant through a filter. Mix 25 cc. of the filtrate (corresponding 
to 10 cc. of the original infusion) with 25 cc. of the indigo solution 
and about 750 cc. of water, and titrate with permanganate. The 
amount used gives the value b; a — b = c; c equals the amount 
of permanganate required to oxidize the tannin. Assume that 
0.04157 gram of tannin (gallotannic acid) is equivalent to 0.063 
gram of oxalic acid. 



XXV. NEUTRAL PRINCIPLES 



These are physiologically active substances which are neither 
acid nor basic and have no distinguishing chemical properties. 
Some are bitter and could, therefore, be classified as bitters, 
except for their toxicity and pharmacologic actions. They re- 
semble the glucoside closely, but on hydrolysis do not decompose 
into sugar; although santonin sometimes contains sugar as an 
impurity. The classification of neutral bases, therefore, is in- 
definite and includes those chemically nondescript principles of 
neutral reaction which are physiologically active. Digitalis, 
si rophanthus, and even alkaloidal salts from the chemical stand- 
point might be included, except that they have chemical proper- 



' 



NEUTRAL PRINCIPLES 



219 



ties that place them in more sharply defined chemical groups. 
The chief neutral principles are: 

1. Santonin 

2. Pier o toxin 

3. Elaterin 

4. Chrysorobin 

Santonin, C15H18O3, is obtained from wormseed and forms as 
crystalline, colorless, bitter, shining leaflets, which melt at 170°C, 
and are soluble in 500 parts of cold water. It is used as an anthel- 
mintic, especially for roundworms. 

It is the internal anhydride (lactone) of santonic acid. 

CH.3 H2 








H— OH 




CH.COOH 



CH.3 CH2 

Santonic acid 



CH< 




H— 



— CH 



;CO 



CH3 

Santonin 
Santonin is a ketone and as such, will react with phenyl hydra- 
zine and hydroxylamine. When used as an anthelmintic a 
slight amount is absorbed and oxidized to oxysantonin C12H18O4. 
Jaffe found this substance in the urine of dogs to the amount of 
5 per cent, of the santonin administered. In rabbits only a 
small amount could be found. In the rabbit's urine beta-oxy- 
santonin was found which is isomeric with alpha-oxy santonin. 
After therapeutic doses (0.06 gram) of santonin human urine is 
reddish and on the addition of KOH, it becomes carmine. 



220 CHEMICAL PHARMACOLOGY 

On treatment with lime water, the urine becomes a scarlet or 
purple color. 

TESTS 

1. Santonin heated with an alcoholic solution of KOH gives a 
carmine color, which soon fades through yellow to colorless. 

2. Santonin heated with concentrated H 2 S0 4 containing a 
drop of ferric chloride becomes pink; 10 milligrams of santonin 
to 1 cc. of the acid is sufficient. 

PICROTOXIN 

Picrotoxin, C 30 H 34 Oi3 is the poisonous principle of cocculus 
indicus. It crystallizes in long colorless needles, M.P. 200°C. 
It has a very bitter taste, and has a marked action on the medulla 
producing spasms that have some resemblance to strychnine 
tetanus. Heated to boiling with 20 times its volume of benzene 
or chloroform, it decomposes into picrotoxin and picrotin, 

C30H34O13 == C15H16O6 + C15H18O7 

The fate of picrotoxin in the body and the manner of its excretion 
is unknown. 

TESTS 

1. Picrotoxin reduces Fehling's solution. Dissolve a little in 
a test tube by the aid of dilute NaOH, and add to dilute boiling 
Fehling's solution. 

2. If it is warmed with a dilute solution 1 per cent. AgN0 3 
containing slight excess of ammonium hydroxide a black precipi- 
tate of metallic silver will be produced. Where only traces of 
picrotoxin are present, the precipitate is colored brown. 

3. On oxidation with a trace of H 2 S0 4 on a porcelain dish, 
picrotoxin becomes orange red and dissolves to a reddish yellow. 

4. H. Meltzer's Test. — One to two drops of a mixture of ben- 
zaldehyde and absolute alcohol added to some picrotoxin powder 
on a watch glass, will produce a red color when a drop of concen- 
trated H2SO4 is added. The alcohol here is added as a diluent 
because H 2 S0 4 produces a brown color with pure benzaldehyde. 
20 per cent, benzaldehyde in absolute alcohol is enough. 



CHRYSOKOBIN 



221 



5. Langley's Test. — Picrotoxin mixed with about 3 times its 
weight of KN0 3 and moistened with a trace of H 2 S0 4 will give 
an intense red color when an excess of strong NaOH is added. 

6. Physiologic Test. — Typical convulsions are produced in the 
frog, but they differ in many respects from those caused by 
strychnine. Picrotoxin spasms cease when the medulla is 
removed while strychnine tetanus continues after ablation of the 
medulla. 

ELATERIN 

Elaterin, C 2 oH 2 80 5 , is the neutral principle of elaterium. It 
consists of two substances, alpha-elaterin, which is levo-rotary 
and inert, and beta-elaterin, the active dextro-rotary substance. 

Elaterin does not exist as such in fruit, but is formed after 
expression by a diastatic ferment acting on a glucoside. Little 
is known of the chemistry of elaterin or its fate in the body. 

CHRYSOROBIN 

Chrysorobin is a mixture of neutral principles from Goa 
powder. The chief principle is chrysophanolanthranol C15H12O3, 
m.p. 204°, an orange yellow, tasteless, odorless powder, very 
irritating to mucous membranes. 

According to Tutin and Clewer, chrysophanic acid has the 
formula 




or dioxmethyl anthraquinone. 



Chrysorobin is the anthranol corresponding to chrysophanic acid 
and has the formula 



222 



CHEMICAL PHARMACOLOGY 

CH 3 OH OH 



OH OH 

Anthranol is oxyanthracene 
OH 



Anthranol 

Commercial Goa powder contains a mixture of neutral principles, 
C30H26O7 and in addition to these described, contains dichrysoro- 
bin C30H23O7 and its methyl ester. Aloin and salicin have been 
classed as neutral principles but they belong definitely to the 
glucosides. 

In the body part of the absorbed chrysorobin is oxidized to 
chrysophanic acid, but most of it is excreted unchanged by the 
kidneys and may cause nephritis. In man slight albuminuria 
has been observed after its application to the skin. 



XXVI. ALKALOIDS 
NITROGEN BASES; PLANT BASES OR ALKALOIDS 



These are all synonymous terms and not sharply defined. The 
property of N in some compounds to change its valence from 3 
to 5, and to unite with acids to form salts is the reason for the 
term nitrogen base. The isolation of a number of such bases 
from plants, led to the term vegetable alkaloids or " plant bases," 
a term which was formerly restricted to those bases in which the 
nitrogen was in combination of pyridine, quinoline, or isoquino- 
line. This excluded many nitrogen bases of obvious alkaloidal 









ALKALOIDS 



223 



reactions, including the caffeine or purine bases, which are now 
generally conceded to be alkaloids. Alka- loid means an alkali- 
like substance. For convenience of study, nitrogen bases or al- 
kaloids in the broad use of the term may be divided as follows : 



(1) Vegetable alkaloids 
derivatives of . . . 



Nature of Nucleus 
Group 1. Pyrrole 

Group 2. Pyridine 
Group 3. Diheterocyclic, 
with a common 
nitrogen atom 

Group 4. Quinoline 
Group 5. Isoquinoline 
Group 6. Glyoxaline 
Group 7. Purine 
Group 8. Cyclic or acyclic 
derivatives of 
aliphatic amines 



Examples 
Hygrine 
Stachydrine 
Coniine 



Atropine, 

Sparteine 

Strychnine 

Papaverine 

Pilocarpine 

Caffeine 



Choline, ar- 
ginine 



(2) Animal bases or 
Alkaloids . . . 



(3) Ptomaines or putre- 
factive alkaloids. 



(4) Purine Bases 

also included under 
1. 



Group 9. Alkaloids of un- 
known constitution 
Epinephrine — a catechol or 
pyrocatechol derivative. 
Choline 
Muscarine 
Betaine 
Neurine 

Trimethyl amine. 
Parahydroxylethylamine and 
other ergot amines. 
Purine 

Hypoxanthine 
Xanthine 
Guanine 
Theobromine 
Caffeine 
Uric acid 



224 CHEMICAL PHARMACOLOGY 



(5) Artificial Bases 
or synthetic alka- 
loids. 



Antipyrine 
Epinephrine 
Cocaine substitutes 



In describing these we will not follow this order in detail. 

GENERAL CHARACTERISTICS OF ALKALOIDS 

1. All alkaloids contain C, H, and N, most of them 0, also. 
Those containing ^0, are solid and crystalline, while those lacking 
O, are liquid and volatile. The liquid and volatile alkaloids may 
be regarded as amines, or substituted ammonias and the solid 
and crystalline, as amides. See test for N, p. 8. 

2. All true alkaloids have an alkaline reaction. The purine 
bases are neutral, to litmus. 

3. All have a bitter taste. 

4. Most of them have marked physiologic or toxic properties. 

5. They form salts by direct addition, as ammonia does. 

6. The free alkaloids are relatively insoluble in water and 
soluble in ether, chloroform, carbon bisulphide, etc. The salts 
have opposite solubilities, they are soluble in water, insoluble 
in ether, chloroform, carbon bisulphate and the like. 

7. The majority are optically active, and turn the plane of 
polarized light to the left. A few, coniine, pelleterine, lau- 
danosine, and pilocarpine are dextrorotary. 

8. They are precipitated by a large number of bodies, which 
because they are much used for this purpose, are called alkaloidal 
reagents. The most important are: 

1. Iodine in KI (LugoPs solution) 

2. Hgl 2 in KI (Meyer's reagent) 

3. Tannic acid 

4. Phosphotungstic acid 

5. Gold chloride 

6. Platinum chloride 

7. Picric acid 

8. Picrolonic acid 

The shapes etc. of the salt crystals, aid in the identification 
of the alkaloid. 

9. Many give color changes on being oxidized with nitric 
acid, potassium chlorate, potassium bichromate, etc. These 
color reactions may be characteristic. 



AMINES 



225 



10. Since all contain N, they will give the tests for N. 

11. In cases of poisoning, they leave no characteristic post 
mortem change. 

CHEMISTRY OF ALKALOIDS 

The vegetable alkaloids are related to ammonia and nearly 
all are tertiary amines. The basicity of the alkaloids, like am- 
monia, is due to the property of nitrogen, changing its valence 
from 3 to 5. This is illustrated in the formation of ammonium 
chloride. 

H 



H 



m 



H + HCl 



H 



The alkaloids form salts in a similar way. 




XXVII. AMINES OR SUBSTITUTED AMMONIAS 

Amines are derivatives of ammonia in which the hydrogen has 
been replaced by alkyl groups. Depending on whether one, 
two, or three hydrogens are replaced, the amines are named 
primary, secondary or tertiary. 



X H 


/CH 3 
X H 


/CH 3 
N^-CH 3 
X H 


/CH 3 

N^~CH 3 

X CH 3 




Methy- 


Dimethyl- 


Trimethyl- 




lamine 


amine 


amine 




(primary 


(Secondary 


(Tertiary 




amine) 


amine) 


amine) 



It is hard to draw a sharp dividing line between the simple 
amines and the alkaloids. 

Secondary and tertiary amines are also known in which the 
N takes part in the formation of a ring. For example, in pyridine 



15 



226 



CHEMICAL PHARMACOLOGY 



H 



H 



H 



or quinoline 



N 




the three 



/ 



II 



hydrogen atoms of N^- — H may be regarded as being replaced 



CH— CH 



by a group 



/ 



CH 



= CH— CH 
which may be considered a tertiary amine. 



H 5 



Piperidine, 



H 5 



H, 



H £ 



H. 



may be classed as a secondary 



NH 



amine. 



Tests for Amines 



1. Like ammonia, they form white clouds of finely divided 
salts, when brought in contact with HC1 or other volatile acid. 
The amines differ from ammonia in being combustible. 

2. The amines can be separated from ammonia, if in solution 
together, by making strongly alkaline with NaOH or Na 2 C0 3 . 
Then the addition of very fine amorphous mercuric oxide, which 
will precipitate the NH 3 , as follows: 

2HgO + NH 3 = Hg 2 N.OH + H 2 
The precipitate may be separated from the amines by filtration. 



AMINES 227 

3. Primary and secondary amines will condense with formalde- 
hyde while tertiary . amines do not. The free bases can then be 
regenerated by hydrolysis, and the difference in the distillation 
temperature allows separation of primary from secondary. 

4. Primary amines all give Hoffman's carbylamine reaction; 
secondary and tertiary amines do not. 

R - NH 2 + CHC1 3 + KOH = R - N = C + 3KC1 + 3H 2 

The disagreeable, indescribable odor is characteristic. 

Another method of distinguishing primary, secondary and 
tertiary amines is to determine the number of alkyl groups with 
which the substance can combine. For example: A substance 
having the formula C3H9N. might be: 

(a) C3H7NH2 — propyl amine — primary 

(b) C 2 H 5x 

yNH — methyl ethyl amine — secondary or 
CH 3 X 

(c) CH 3 v 

CH 3 -^N — trimethyl amine — tertiary 
CH 3 X 

If when heated with an excess of CH 3 I a quaternary compound 
should be formed in each case, with the primary amine this 

would be: C 3 H 7 v 

)>NI or C 6 H 16 NI 
(CH 3 )/ 

C2H5V 
With the secondary it would be: ^Nlor C 5 H H NI 

(CH 3 )/ 
with the tertiary: (CH 3 ) 4 NI or C 4 Hi 2 NI 

The determination of the amount of iodine added will decide 
the question. The titration of the iodine may be done in a 
manner similar to that described under thymol iodide. 

Other tests for the different amines are as follows : 

/ R 

First. — Primary amines N^-H 



228 CHEMICAL PHARMACOLOGY 

When primary amines are treated with nitrous acid HN0 2 , 
they yield alcohols and nitrogen is evolved: 



R. 
+HO 



H 2 

-*R.OH + H 2 + N 2 




This reaction is analogous to the reaction of nitrous acid with 
ammonia, which yields nitrogen and water : 

.H 2 = N 2 + 2H 2 



NH 3 + HN0 2 = H. 
HO 







Second. — Secondary amines. When these are treated with 
nitrous acid they yield nitroso amines: 

R x R x 

pN.HHO - NO = ^N - N = + H 2 
W W 

Third. — Tertiary amines either do not react with nitrous acid 
or are oxidized by it without the formation of definite products. 

QUATERNARY AMMONIUM BASES 
Ammonia, NH 3 , will unite directly with HC1 to form 

/ H 

Nf-H 

^H 

CI 

In a similar way, tertiary amines unite with alkyl iodide to form 
quaternary ammonium iodides or quaternary ammonium bases. 
The physiological action of these quaternary bases differs from the 
trivalent type. The characteristic action is a paralysis of the 
motor nerve ending to striated muscle. This action seems to 
depend more on the physical configuration of the molecule than 
upon the chemical elements, since phosphorus or arsenic may be 
substituted for nitrogen. This paralytic action is also exerted 
by alkaloids in which the nitrogen is quinquivalent, such as 
curare, methyl strychnine, methyl quinine, methylmorphine, 
ethyl brucine, and ethyl nicotine. 



AMINES N 229 

Sources of Amines 

Amines occur in nature as the decomposition products of 
proteins, and the decarboxylation of amino acids, e.g. : 

CH 2 NH 2 COOH->CH 3 NH 2 + C0 2 
CH 3 CH 2 NH 2 COOH-^CH 3 CH 2 NH 2 + C0 2 

In this way amines corresponding to all the known amino 
acids are thought to have arisen. This process is favored by the 
presence of some peptone which serves as a source of nitrogen 
for the bacteria and in this way prevents deaminization. They 
may also be prepared synthetically; if a concentrated solution 
of ammonia be heated in a sealed tube with an alkyl iodide, the 
corresponding amine is formed : 

NH 3 + CH 3 I-+NH 2 (CH 3 ) + HI 

By further action of the methyl iodide, the other H atoms of 
the ammonia may be substituted. 

NH 3 + CH 3 I = CH 3 .NH 2 .HI . 

Methylamine hydriodide. 
CH 3 .NH 2 + CH 3 I = (CH 3 ) 2 NH.HI 

Dimethylamine hydriodide. 
(CH 3 ) 2 NH + CH 3 I = (CH 3 ) 3 N.HI 

Trimethylamine hydriodide 
(CH 3 ) 3 N + CH 3 I - (CH 3 ) 4 N.I 

Tetramethyl ammonium iodide. 

Trimethyl amine can also be formed by heating ammonium chlo- 
ride with formalin in an autoclave at 120-160°C. (cf . urotropine) 

2NH 3 + 9CH 2 -> 2(CH 3 ) 3 N + C0 2 + 3H 2 

Amines may also be prepared by the reduction of nitro com- 
pounds 

CH 3 N0 2 + 3H 2 -> CH 3 NH 2 + 2H 2 
Nitro methane methylamine 

This is a common method of obtaining phenyl amine or aniline 

C 6 H 5 N0 2 + 3H 2 -> C 6 H 5 NH 2 + 2H 2 
Nitro-benzene Aniline 



230 



CHEMICAL PHARMACOLOGY 



These aromatic amines may also be primary, secondary or 
tertiary as in case of the alkyls 



Primary 


Secondary 


Tertiary 


yCeHs 


/C6H5 
N^-CH 3 
\ H 


•CeH 5 
N^-CHa 
X CH 3 


phenylamine or Ani- 
line 


phenyl 
Methylamine 


phenyl 
Dimethylamine 


/C 6 H 5 


/Cells 
N^C 6 H 5 


/CeH 5 
N^C 6 H 5 

X C 6 H 5 


Aniline or phenyl- 


Diphenylamine 


Triphenylamine 


amine 







The aromatic amines are more active pharmacologically than the 
aliphatic. 

Amines may also be prepared by reduction of nitrils 

CH 3 CN + 4H -> CH 3 CH 2 NH 2 
Methyl nitrile 

C 6 H 5 CN + 4H -> C 6 H 6 CH 2 NH 2 
Benzo nitrile Benzyl amine 

The Physiological Action of the Amines 

When ammonia is injected intravenously or when given other- 
wise in rather strong solution it stimulates respiration and by 
stimulation of the central nervous system may cause convulsions. 
As the H atoms of ammonia are replaced by alkyl radicals, the 
stimulating action is much diminished, and the extent of the 
diminution increases with the molecular weight of the substi- 
tuted alkyl. 

Alkyl groups are cerebral depressants and the hypnotic action 
of alcohol, ether, etc., is due to the alkyl groups. When quater- 
nary amine bases are formed, the action becomes paralytic due 
to a paralysis of the motor nerve ends in a manner similar to 
that effected by curara. The nitrogen atom in the quaternary 
amine has little to do with the curara action, since the corre- 
sponding phosphorus and arsenic compounds have a like action. 

Many amines (substituted ammonias) raise the blood pressure 



AMINES 231 

after the manner of nicotine and epinephrine. Barger and Dale 
have made a rather exhaustive study of the physiological effects 
of the amines on the rise in blood pressure, the action on the uterus, 
pupil, etc. (Journal of Physiol., 1910, 41, p. 19) and have com- 
pared* the action on these locations with that of epinephrine. 
Of the aliphatic amines, only the higher open chain primary 
amines such as amyl amine, C5H11NH2, and hexyl amine, 
C 6 Hi 3 NH 2 , produced a marked rise in blood pressure. Isobutyl 
amine, C4H9NH2, is the first to cause any significant rise. The 
normal straight chained compounds were more effective than 
the isocompounds. Cadaverine, NH 2 (CH 2 )5NH 2 , the only 
diamine examined, caused a fall of blood pressure instead of a 
rise. Trimethyl amine and tetramethyl amine were inactive, 
and of little physiological importance. 

A large number of aromatic compounds without a phenolic OH 
and containing an amine aliphatic side chain were investigated, 
and it was found that only when the amino group in the side 
chain is attached to the second carbon from the ring is there a 
marked epinephrine — like action. Beta-phenyl ethyl amine 
produced all the actions of epinephrine. 

Amines with one phenolic hydroxyl group in the ortho position, 
such as ortho hydroxyphenyl ethyl amine 



CH 2 .CH 2 NH 2 , 



HO 



are no more active than phenyl ethyl amine itself. The para 
compound which is present in ergot (tyramine) and may also be 
prepared' by heating tyrosin 



>CH 2 CH.COOH 

NH 2 
has a similar action. 

The pressor or blood pressure raising property in this case 
depends on the basic property of the substance, for acetyl p. 
hydroxyethyl amine 



232 CHEMICAL PHARMACOLOGY 



H0< >CH 2 .CH 2 NH CO.CH3 



is inactive. The tyrosin ester 



■CH 2 .CH^ 

X NH 2 

is also inactive. Methylation or ethylation of the amino group 



HO< >CH 2 .CH 2 NH.R 



changes the action but slightly and the alkaloid hordenine, which 
is the tertiary base, has a very weak action 



HO< >CH 2 .CH.N(CH 3 ) 2 



Amines with two phenolic hydroxyl compounds were tested 
and their comparative effect on the blood pressure is as follows 
(arranged after Percy May Synthetic Drugs) : 

Amines with Two Hydroxyl Compounds. — The following 
compounds in which the two hydroxyl groups are in the 3-4 
position were tested: 

(a) Derivatives of Aceto-catechol (Ketones) 

Ratio of 

(1) Amino-aceto-catechol, Activity 

(HO) 2 C 6 H 3 ~ CO— CH 2 — NH 2 . 1 . 50 

(2) Methylamino-aceto-catechol — 

(HO) 2 C„H 3 — CO— CH 2 — NH— CH 3 . 

(3) Ethylamino-aceto-catechol — 

(HO) 2 C H 3 — CO— CH 2 — NH— C 2 H 5 . 2.25 

(4) Propylamino-aceto-catechol — 

(HO) 2 C c H 3 — CO— CH 2 — NH— C 6 H 7 0.25 

' (5) Trimethylamino-aceto-catechol chloride — 
(HO) 2 C 6 H 3 — CO— CH 2 — N (CH ,) 3 C1 . 



AMINES 233 

(6) Derivatives of Ethyl-catechol 

(6) Ainino-ethyl-catechol, 

(HO) 2 C 6 H 3 — CH 2 — CH 2 — NH 2 . 1 . 00 

(7) Methylamino-ethyl-catechol — 

(HO) 2 C 6 H 3 — CH 2 — CH 2 — NH— CH 3 . 5 . 00 

(8) Ethylamino-ethyl-catechol — 

(HO) 2 C 6 H 3 — CH 2 — CH 2 — NH— C 2 H 5 . 1 . 50 

(9) Propylamino-ethyl-catechol — 

(HO) 2 C 6 H 3 — CH 2 — CH 2 — NH— C 3 H 7 . 25 

(10) Trimethylamino-ethyl-catechol chloride — 

(HO) 2 C 6 H 3 — CH 2 — CH 2 — N(CH 3 ) 3 C1 

(c) Derivatives of Ethanol-catechol (Secondary 
Alcohols) 

(11) Amino-ethanol-catechol — 

(HO) 2 C 6 H 3 CH (OH)— CH 2 — NH 2 . 50 . 00 

(12) Methylamino-ethynol-catechol (adrenaline) — 

(HO) 2 C 6 H 3 CH(OH)— CH 2 — NH— CH 3 35.00 

The main conclusions of Barger and Dale from their Investiga- 
tion of the amines are : 

1. An action simulating that of the true sympathetic nervous 
system is not peculiar to adrenine, but is possessed by a large 
series of amines, the simplest being primary fatty amines. We 
describe all such amines and their action as "sympathomimetic." 

2. Approximation to adrenine in structure is, on the whole, 
attended with increasing intensity of sympathomimetic activity, 
and with increasing specificity of the action. 

3. All the substances producing this action in characteristic 
'manner are primary and secondary amines. The quaternary 
amines corresponding to the aromatic members of the series 
have an action closely similar to that of nicotine. 

4. The optimum carbon skeleton for sympathomimetic activity 
consists of a benzene ring with a side chain of two carbon atoms, 
the terminal one bearing the amino group. Another optimum 
condition is the presence of two phenolic hydroxyls in the 3-4 
position relative to the side chain; when these are present, an 
alcoholic hydroxy 1 still further intensifies the activity. A phenolic 
hydroxyl in the 2 position does not increase the activity. 

5. Catechol has no sympathomimetic action. 



234 



CHEMICAL PHARMACOLOGY 



6. Motor and inhibitor sympathomimetic activity vary to 
some extent independently. Of the catechol bases those with 
a methylamino group, including adrenine, reproduce inhibitor 
sympathetic effects more powerfully than motor effects: the 
opposite is true of the primary amines of the same series. 

7. Instability and activity show no parallelism in the series. 

The amines are very slightly toxic and their ultimate fate es- 
pecially that of the lower members in the body is perhaps similar 
to ammonia, urea and carbon dioxide being the ultimate products. 
In some cases various intermediate products are formed. Ewins 
and Laidlow found that one-half the amount of p. hydroxy phenyl 
amine given by mouth to dogs was excreted in the urine as para 
hydroxy phenyl acetic acid. This same conversion of the amine 
into the acid occurred when it was perfused through the rabbit's 
liver, but when perfused through the isolated heart it was com- 
pletely destroyed without the formation of acid. In the vast 
majority of the cases, however, little is known of the fate in the 
body. In view of the great activity of histamine and its probable 
relation to anaphylactic shock and to the toxicity of proteins as 
emphasized by Vaughan, many think that a detailed investi- 
gation of the fate of the higher amines, especially those like his- 
tidine and the more complex peptamine will go far to explain 
symptoms now classified as ptomaine poisoning or other equally 
vague terms. 

ALKALOIDS DERIVED FROM ALIPHATIC AMINES 
A number of important alkaloids are aliphatic derivatives or 
combinations. The most important in pharmacology are: 
1. Epinephrine 



2. Arginine 

3. The putrefactive alkaloids 


Betaine 
Choline 
Muscarine 


Putrescine 
Cadaverine 


4. Ergot alkaloids 

5. Sinapine 

6. Hordenine 


Tryamine, 
Histamine, 
Ergotoxine, 
Isoamylamine. 




Epinephrine or the 
a derivative of para hj 


pressor pi 
rdroxyphe 


inciple of the adrenal glands is 
nylethyl amine 



AMINES 



235 



HO 



>CH 2 CH 2 NH ; 



and has the formula / 
OH— <^ 

/ 



NcH(OH)CH 2 .NH.CH 5 



OH 

It was first isolated by Abel in 1879 and 1899 (Zeit. f. Physiol. 
Chem., 1898, 28, 318; and Am. Jour. Physiol., 1900, 3, XVII) 
and by Takamine who obtained it in crystalline form and from 
its decomposition thought he obtained catechol and pyrocate- 
chuic acid. These products have been used in the preparation 
of synthetic epinephrine. It has since been isolated and analyzed 
by others. It has also been prepared synthetically. The natural 
product is a slightly yellowish powder, and levo-rotatory. The 
synthetic product is optically inactive and resolvable into a 
dextro and levo form. Th natural product is twice as effective 
as the synthetic judged by its action in raising the blood pres- 
sure. The levo form is about 12 times as active as the dextro. 
The action on the blood pressure is due to a stimulation of the 
sympathetic nerve endings to the heart and blood vessels. Its 
action in any location can be predicted if we know the result of 
stimulation of the regional sympathetics. In the intestine and 
bronchioles, stimulation of the sympathetics causes a relaxation 
and dilation; and in these regions, epinephrine has a like effect. 
Because it mimics the action of the sympathetics, Barker and 
Dale suggest the term sympath-o-mimetic, to describe its action. 
The synthesis of epinephrine has been effected by Friedman 
as follows : 

OH OH 



OH + CLCO.CHaCl 



OH 



Catechol + Chloracetylchloride 



CO.CH 2 Cl 
chloracetyl catechol 



236 



CHEMICAL PHARMACOLOGY 

OH 



+ HNH-CH- 



OH 






CO.CH 2 .NH.CH 3 

Methylamine Methyl amino aceto catechol or adrenalone 

OH 



+ H s 



OH 



HC(OH)CH 2 .NH.CH 3 

Epinephrine. 

Epinephrine has been prepared by another method, starting 
with pyrocatechuic aldehyde 



OH 



•CHO + HCN 



OH 

Pyrocatechuic 
aldehyde 



OH 



CHOH.CN + Reduction 



OH 



OH 



COHH.CH 2 .NH 2 which on methylation 



OH 



OH< 



CHOH.CH 2 .NH.CH ; 



OH Epinephrine 



AMINES 237 

This is the accepted formula — others suggested are : 



CH 2 CHOH.NH.CH 3 and 




CH.NH.CH; 



CH 2 OH 



In favor of the accepted formula I is the fact that methyl- 
amino aceto catechol or adrenalone from which adrenaline may 
be prepared by reduction, is formed by the action of methyl 
amine on chloracetyl catechol 



HO< >— CH 2 — CH 2 .N(CH 3 ) 2 



Hordenine. 

Hordenine, an alkaloid in malt, is very closely related to epine- 
phrine in structure, but its action is more like phenol than epine- 
phrine. It is only slightly toxic : 

1 gram per kilo per os in a dog or rabbit causes some rise in 
blood pressure and acceleration of the pulse. It acts both on 
sympathetic and para sympathetic endings, and also centrally. 
After a fatal dose, which for a dog is 0.3 gm. per kilo intraven- 
ously, death occurs from respiratory failure — similar to phenol. 

Epinephrine Tests 

1. To a dilute solution of adrenaline chloride or an extract of 
the gland, add a few drops of ferric chloride. An emerald green 
color develops but this is quite transient (phenolic reaction). 

2. To a solution add some sodium carbonate. A reddish color 
is formed. Alkalies destroy the physiologic effect of the substance 
rapidly. 

3. Physiological test: 1 cc. 1-10,000 solution injected into the 
vein of a mammal will cause a great rise in blood presure. 



238 CHEMICAL PHARMACOLOGY 

ARGININE 

Arginine is physiologically inactive in animals, consequently is 
of little interest from a purely pharmacodynamic point of view. 
Chemically it is alpha amino guanidine valerianic acid. 

NH 2 

I- 
C = NH 

I 
N— H 

I 
H— C— H 

I 
H— C— H 

H— C— H 

I 
H— C— NH 2 

=C— OH 

All proteins contain arginine, and the head of salmon sperm 
yields nearly 90 per cent. Arginine, lysine and histidine have 
been called hexone bases, by Kossel, because they contain 6 
carbon atoms, and he thought proteins were built up of such 
amino acids in a manner similar to the formation of complex 
carbohydrates from hexoses. The relationship of proteins to 
alkaloids is again apparent here. 

The Fate of Arginine in the Body 

By the action of so-called carboxylase bacteria, which decar- 
boxylate arginine, agmatine is formed : 

NH 2 — C(NH)— NH.CH 2 (CH 2 ) 2 CHNH 2 .COOH = 
Arginine. 
C0 2 + NH 2 .C(NH).NH.CH 2 (CH 2 ) 2 .CH 2 NH 2 
Agmatine. 

Agmatine has also been obtained from ergot and has been 
synthesized by Kossel. It is regarded as amino butylene guanid- 
ine. According to Dale and Laidlow agmatine contributes but 






AMINES 239 

little to the activity of ergot. It acts like histamine but is only 
1/50 as active. Arginine may also be split in the body by an 
enzyme into urea and ornithine, i.e. alpha d-diamino valeric acid. 

7 NH 2 NH 2 

NH = (/....--"" | 

HO X NH— CH 2 — (CH 2 ) 2 — CH— COOH 

H 

NH 2 NH 2 

I I 

CO + NH 2 — CH 2 — (CH 2 ) 2 — CH-COOH 

NH 2 

This change may also be accomplished by boiling with alkali. 
A further decomposition of the ornithin to ammonia and carbon 
dioxide may occur. 

PTOMAINES OR PUTREFACTIVE ALKALOIDS 

Ptomaines or putrefactive alkaloids are products of the putre- 
faction of meat. They are basic bodies, usually amines'of simple 
constitution, such as methyl amine CH 3 NH 2 — dimethyl amine 
(CH 3 ) 2 NH or trimethyl amine (CH 3 ) 3 N. 

Many ptomaines are toxic, others non-toxic. The toxicity 
may be due in part to ptomaines directly and in part to associ- 
ated unknown toxins. 

In their reactions ptomaines may resemble some alkaloid. 
This pharmacologic and chemical resemblance may make the 
identification of the alkaloids difficult. The similarity, however, 
is usually confined to one of the reactions of the alkaloid, and 
never extends to all the reactions characteristic of any particular 
alkaloid. Ptomaines have been found that show certain re- 
semblances to confine, nicotine, codeine, strychnine, veratrine, 
atropine, hyoscyamine and morphine; but as stated above these 
resemblances are frequently confined to one reaction and never 
in any case agree with all the characteristic reactions of the 
alkaloid. 

Ptomaines are of limited importance as medicines, having a 
toxicologic interest only. Their great toxicity is probably due 



240 CHEMICAL PHARMACOLOGY 

to the inability of the body to oxidize them, even in minute 
amount. 

The most important ptomaines are: 



Putrescine 


NH 2 (CH 2 ) 4 NH 2 


Cadaverine 


NH 2 (NH 2 ) 5 NH 2 


Choline 


N(CH 3 ) 3 OH 




CH 2 CH 2 OH 


Muscarine 


N(CH 3 ) 3 OH 




CH 2 CHO 


Betaine 


N(CH 3 ) 3 

1 >o 


Neurine 


N(CH 3 ) 3 OH 




CH = OH 






. Choline, muscarine, betaine, and neurine are sometimes called 
the betaines. 

Putrescine: (from putresco, to rot or putrefy), or tetramethy- 
lene diamine — 

NH 2 .CH 2 .CH 2 .CH 2 .CH 2 .NH 2 

occurs associated with cadaverine. It was first obtained from 
putrefying human internal organs. It has also been found 
in the excreta of cholera patients, and in the urine in cases of 
cystinuria. Carbohydrate diet lessens the amount excreted in 
these cases, while meat diet increases it. This points to protein 
as the source of putrescine. Normal feces do not contain it. 
The use of salol, sulphur, and other intestinal antiseptics does 
not appreciably influence the amount excreted. Garcia, how- 
ever, has shown that when cane sugar is added to putrefying 
meat and pancreas in vitro, less diamine is formed. The bacteria 
forming the diamines apparently live on the sugar in preference 
to the protein. Sugar or carbohydrate for this reason has been 



AMINES 241 

advocated as the preferable diet in many cases of gastrointes- 
tinal putrefactions. 

The relation of putrescine to cystinuria is but little under- 
stood. It was suggested that putrescine and other diamines 
united with cystin to prevent its oxidation. When diamines 
are fed to dogs no cystinuria occurs, and the formula of cystine 

H H 

H — C— S S C— H 

NH 2 — C— H H— C NH 2 

I I 

O = C— OH = C— OH 

does not suggest an origin from the diamines. 

The source of putrescine is most probably directly from orni- 
thine or a, e, diamino valeric acid. 

NH 2 .CH 2 .CH 2 .CH 2 .CH 2 .NH.COOH-> 
ornithine 

NH 2 .CH 2 .CH 2 .CH 2 .CH 2 .NH 2 . + C0 2 

putrescine. 

Putrescine has also been prepared synthetically. Addition 
or substitution products can be readily formed. The tetramethyl 
derivative N(CH 3 ) 2 (CH 2 ) 4 ]Nr(CH3) 2 , is much more poisonous 
than putrescine, and resembles muscarine in action. The symp- 
toms are: nausea, vomiting, salivation, increase then decrease of 
respiration, contracted pupils, diarrhoea and collapse. Atropine 
will counteract many but not all of these symptoms. 

Cadaverine or penta-methylene diamine is found associated 
with putrescine and is formed similarly. It is probably formed 
from lysine or a, e, diamino caproic acid by decarboxylation: 

NH 2 .CH 2> CH 2 .CH 2 .CH 2 .CHNH 2 COOH— 
lysine 

NH 2 .CH 2 .CH 2 .CH 2 .CH 2 .CH 2 .NH 2 . + C0 2 

and is probably identical with so-called animal coniine which 
has been isolated from cadavers. It may produce marked in- 
flammation and necrosis, and like turpentine and some other 

-16 



242 CHEMICAL PHARMACOLOGY 

drugs, can cause suppuration in the absence of bacteria. With 
putrescine it probably causes the cystitis of cystinuria. It is 
not very poisonous however,' — large doses will kill mice, but it is 
relatively non-poisonous to dogs. 

By heating pentamethylene hydrochloride piperidine may be 
formed which has a definite toxic action: 



.CH 2 .CH 2 NH 


H 


+ HC1 


NH 2 


CH 2 


/\ 


CH 2 CH 2 


| | + NH 4 C1 


CH 2 CH 2 


\/ 


NH * 


Piperidine. 





By oxidation of piperidine to pyridine the toxicity is again 
markedly reduced. 

Choline (chole-bile). — Choline is partly amine and partly 
alcohol. It is found as a constituent of lecithin, which occurs 
especially in nervous tissue, egg-yolk, seeds, and elsewhere. It 
is also found in ergot, and in many-plants. Its composition is 
shown by its synthesis from trimethylamine and ethylene oxide 
in aqueous solution 

(CH 3 ) 3 N + CH 2 . CH 2 .CH 2 .CH 2 OH 

+ H 2 = (CH 3 ) 3 N( 



X)H Choline 

It is related to muscarine and to neurine : 

.CHs.COH .CHrCH, 

(CH 3 ) 3 N< (CH 3 ) 3 N( 

X OH X OH 

Muscarine Neurine 

While choline is but slightly toxic, its dehydrated product neurine 
is extremely toxic. In the formation of neurine from choline, by 
the elimination of a molecule of water, a double-bonded carbon 



CHOLINE 



243 



combination is formed. If this double-bond is changed to a 
triple bond by the formation of 



(CH 3 ) 3 N: 



CiCH 



OH 



the product is still more toxic. See p. 148 for influence of triple 
bond. 

The formation of choline from lecithin can be seen from the 
formula of lecithin, R and R/ being similar to dissimilar acid 
radicals : 

CH 2 OR 
CHOR' 



.OH 

CH.O— P( = O 

X 0— CH 2 .CH 2 .N(CH 3 ) 3 .O.H 



Lecithin, however, cannot be regarded as the only source of 
choline in plants because it occurs where no lecithin has been 
found — as in the seeds of white mustard, sinapin giving rise to 
choline as follows : 

C 16 H 23 N0 5 + H 2 = C 5 H 15 N0 2 + C n H 12 5 
Sinapin Choline Sinapic acid 

Betaine or trimethyl-glycocol 

N.(CH 3 ) 3x 

I 
CH 2 .CO 



:0 



gets its name because it is found free in the sap of the sugar beet 
Beta vulgaris. Betaine is the anhydride of hydroxytrimethyla- 
mine-acetic acid: 



N.(CH 3 ),.— 
CH 2 .COO 



OH 
H 



244 CHEMICAL PHARMACOLOGY 

The alkaloid stachydrine 



,CH 2 — CH.CO 



ch 2 ' ;>o 

X CH 2 — N.(CH 3 )/ 

one of the pyrrolidine alkaloids, is also a derivative of this sub- 
stance being a dimethyl betaine of pyrrolidine. Betaine is 
physiologically inactive when given by mouth, hypodermically it 
acts like choline. It occurs in large amounts in the muscles of 
cephalopods and has been isolated from human urine and has 
been prepared synthetically. Betaine is excreted unchanged and 
cannot therefore act as a food. 

Muscarine is a tertiary amine and an aldehyde, while choline 
is the corresponding amine with an alcohol. Very few amino 
aldehydes or amino ketones are known. 

Amino acetaldehyde — CH 2 NH 2 .CHO is a very unstable corn- 
compound. Muscarine is thought to be the corresponding 
trimethyl ammonium base : 



CH 2 — N(CH 3 ) 3 .OH 






M 


or 


CH 3X / CH 2 .CH(OH) 2 


C<^ + H 2 
^0 




CH/ \)H 



The action of muscarine is very similar to pilocarpine or to 
arecoline. It causes: 

1. A marked slowing of the heart by stimulation of the vagus 
endings. 

2. A constriction of the pupil, due to stimulation of the third 
nerve endings. 

3. Marked gastric and intestinal peristalsis leading to vomiting 
and diarrhoea, also asthmatic respiration. 

4. Marked salivation due to stimulation of the endings of, 
the chorda tympani nerve. 

Most of these actions may be neutralized by a small dose of 
atropine. 

ERGOT ALKALOIDS 

In recent years much has been done to make clear the composi- 
tion of the active principles of ergot. These active principles 



ERGOT AMINES 245 

consist of alkaloids and amines. The chief alkaloids are ergo- 
tinine and ergotoxine. These are readily interconvertible. 
Ergotinine is inactive, but its hydrate ergotoxine is active — 

C35H 3 90 5 N 5 + H 2 -» C 3 5H4i0 6 N5 
Ergotinine Ergotoxine 

Both of these alkaloids on destructive distillation give isobutyl 
form amide— (CH 3 ) 2 CH.CO.CO.NH 2 . 

Beyond this little is known of their constitution. Their fate 
in the body is also unknown. Ergotoxine, along with hista- 
mine, is responsible for practically the whole action of 
ergot in therapeutics. It acts very much like adrenaline 
from which it differs by stimulating only the motor myoneural 
junctions of the sympathetic nerves while it does not act on the 
inhibitors. Dale found that in large doses ergotoxine paralyzes 
the augmentor elements only, and that adrenaline after ergo- 
toxine often causes a fall of blood pressure. This phenomenon he 
called "vaso motor reversal." 

ERGOT AMINES 
Isoamylamine 

CH 3 

)CK CH 2 CH 2 . NH 2 
CH/ 

is an ergot amine, and results from the putrefaction of proteins. 
It probably arises from leucine, 



CH 3 



V^H— CH 2 CH.COOH 



NH 2 

by a splitting off of carbon dioxide. 

When injected intravenously isoamyline raises the blood pres- 
sure. The amount present in ergot is too small to be of any 
significance in ergot action. Isoamylamine hydrochloride has 
been employed to some extent as an antipyretic. 

Beta-iminoazolylethylamine-4-meta-amino, ethyl glyoxaline or 
histamine is another ergot amine. It is derived from histidine 
by the action of putrefactive bacteria— 



246 



CHEMICAL PHARMACOLOGY 



CH— NH, 



-N' 



:CH 



CH 2 > 

CH.NH 2 

COOH 

Histidine or a, amino 0, imino- 
azole propionic acid 



CH— NIL 

II >H 

c w + co 2 

CH 2 

CH 2 .NH 2 

Histamine /S, 
iminoazole ethyl-amine 



Histamine stimulates the uterine muscle directly, and is one of 
the important ergot principles. It also stimulates the bronchi- 
oles which are highly sensitive; less so, the intestine arteries and 
spleen. Its action resembles pituitrine. Histamine dihydro- 
chloride, C 5 H9N 3 .2HC1, is readily soluble in water, and is used 
in the standardization of pituitrine. One part of betaimino- 
azolylethylamine hydrochloride (histamine hydrochloride) in 
1:20,000,000 has the same activity on the isolated uterus of the 
virgin guinea pig as 1 to 20,000 solution of standard pituitary 
extract. 

Histamine is precipitated by phosphotungstic acid, by am- 
moniacal silver solutions, and by mercuric chloride in alkaline 
solution. On boiling with bromine water it gives a claret color. 

Parahydroxy phenyl ethylamine or tyramine : 



OH< 



CH 2 .CH 2 .NH< 



is of especial interest in medicine as being one of the active in- 
gredients of ergot. It has also been isolated from putrid meat. 
It gets the name tyramine from the fact that it may be prepared 
from tyrosin: 



OH< 



OH—OH? 



COOH 



NH S 



PYKIDINE ALKALOIDS 



247 



which eliminates C0 2 on heating. Tyramine like epinephrine 
acts on the sympathetic endings, and unlike epinephrine it 
apparently acts more on the constrictor endings and little on 
the dilators. 



PYRIDINE ALKALOIDS 

Pyridine is a colorless mobile liquid, sp. gr. 1.003 at 0°C. 
B.P. 115°. It is an exceedingly stable and chemically inactive 
substance with a pungent characteristic odor, and may be heated 
with nitric or chromic acid without undergoing change. It is 
formed by the destructive distillation of many nitrogenous or- 
ganic substances, especially coal tar and bone oil. 

CH 



Pyridine, CH 



CH 



CH 



CH 



like nicotine, is a highly toxic 

substance. 



N 

In order to name the substitution products, its various 
positions are named in relation to the (N) : 




Since piperidine is formed from pyridine by reduction, the reverse 
change can also be made and pyridine formed from piperidine 
by oxidation. In the formation of pyridine, pentamethylene 
diamine hydrochloride is converted into piperidine and this in 
turn is oxidized to pyridine : 



248 



CHEMICAL PHARMACOLOGY 



yCHo CH 2 v 

CH,/ \NHIH 



\ 



CH 2 -CH 2 -|NH 2 HC1 



Pentamethylene-diamine 

hydrochloride 

+ 30 



HO 



CH 



N 



yCH 2 V 

H 2 C X X CH 2 



H 2 Cv yCH 2 

X NH X 

Piperidine 



CH 



hc, 



/ 



CH 



N N 

Pyridine 

The toxicity of the pyridine homologues increase with increase 

in molecular weight through picoline or methyl pyridine, lutidine 

or dimethyl, collidine or trimethyl to parvoline C 5 NH(CH 3 ) 4 or 

quatramethyl pyridine, which is eight times as toxic as pyridine. 

Pyridine can be formed synthetically, by dry distillation of 

pentamethylenediamine. It may be prepared by boiling the 

alkaloid piperine with alcoholic potash. The decomposition is 

expressed by the formula: 

C 17 H 19 3 N + H 2 = C 6 HnN + C 12 H 10 O 4 
Piperine Piperidine piperic acid. 

Methyl pyridine may occur in small quantities in the tissues 
probably derived from vegetable foods and from pyridine — con- 
taining plants, like tobacco. His (Arch f. exp. pharm., 1894, 
vol. 22, p. 247, 281) confirmed by Cohn (Zeit. physiol. Chem., 
1894, vol. 18, p. 112) found that pyridine is eliminated in the 
urine as methy pyridil ammonium hydroxide 



/ N \ 
CH/ X 0H 

This occurrence of methylation in the animal body is a rare 



METHYLATION IN THE BODY 249 

and interesting phenomenon. Hoffmeister states that after 
feeding an animal tellurium compounds, tellurium dimethide 
Te(CH 3 )2. is excreted in the urine. Methylated compounds as 
a rule when introduced into the body are demethylated. Caf- 
feine loses successively one, two and three methyl groups. Since 
methylation increases the toxicity of pyridine one must feel some 
doubt of its methylation in the body. 

NATURAL METHYLATED COMPOUNDS IN THE BODY 

Creatine is methyl guanidine acetic acid. Creatinine is the 
anhydride of this. These are the most important methylated 
bodies that occur normally in the urine. Creatine is unquestion- 
ably formed from amino acids, but no methylated amino acids 
occur in the body and the process of methylation though not 
known is perhaps similar to that occurring in plants. Methyla- 
tion in plants is a common occurrence and it appears probable that 
methyl compounds are formed by the action of ammonia and 
formaldehyde: 

2NH 3 + 3CH 2 = 2NH 2 : CH 3 + C0 2 + H 2 

This reaction can be readily carried out in the laboratory. 
Formaldehyde has been demonstrated in plants; but its pres- 
ence in the animal body, however, has not been proven. 
Consequently, if this be the mechanism in plants, there is still 
some doubt how methylation takes place in animals. 

In the plant, photo chemical reactions must play an important 
part in such vital processes. 

The Fate of Creatine and Creatinine in the Body 
As stated above some of these bodies occur in the urine. The 
amount of creatinine in the urine remains constant no matter 
how the protein of the diet varies. This led Folin to distinguish 
between exogenous metabolism or the metabolism of food stuffs 
and endogenous metabolism or that due to the breaking down of 
the body protein. Creatinine represents the endogenous metab- 
olism. Creatine is destroyed in the tissues. The mechanism 
of this oxidation is not known, but it has been suggested that it is 
first converted into creatinine, and then destroyed. Folin 
found, however, that creatinine administered is not oxidized; 
but all is eliminated in the urine. 



250 



CHEMICAL PHARMACOLOGY 



Hydrogenation of pyridine results in the formation of piperidine 
or hexahydro pyridine or 

H 2 



H 5 



H 5 



H s 



H< 



NH 

which has an imide group NH and is a secondary amine. 
Piperidine is a colorless oil, with unpleasant odor and strong basic 
properties. Pyridine is but slightly toxic and lowers the blood 
pressure, but piperidine is very toxic and raises the blood pressure 
with general paralysis of central origin. Its total action is much 
like coniine, which is propyl piperidine. Large doses exert a 
curara action on the motor nerve ends. The action of piperidine 
compared with related compounds shows the toxic influence of 
the imide group in the molecule. 



N NH NH 

Pyridine Piperidine Pyrrole 

Pyridine is less toxic than either piperidine or pyrrol, and colli- 
dine is less toxic than coniine. 
CH 3 



CH : 



CH- 



CH2 CH2 CH3 



N 
Collidine 



NH 
Coniine 



ALKALOIDS 251 

Piperidine because it is readily oxidized in the body, does not 
give the methyl synthesis that pyridine undergoes in the body. 
The principal pyridine alkaloids are: 

Coniine from conium maculatum 
Nicotine from nicotina tabacum 
Atropine from atropa belladonna 
Cocaine from Erthroxylon coca 
Morphine from Papaver somniferum 
Narcotine from Papaver somniferum 
Quinine from Cinchona and remija 
Strychnine from Strychnos nux vomica 
Brucine from Strychnos nux vomica 

It is possible to place some of these alkaloids also under other 
heads, because they may contain other nuclei. For example 
quinine and strychnine also contain the quinoline nucleus, which 
is a combination of pyridine and benzene. 

The tests for the pyridine nucleus are: 

1. Potassium ferrocyanide precipitates the base. This product 
is rather insoluble and the pure base can be prepared from it. 

2. When the pure base is treated with platinum chloride a 
double salt, (CsHsN^H^Pt.Cle, is formed. This is soluble in 
water, but hydrochloric acid is evolved and a yellow insoluble 
compound (C 5 H 5 N)Pt.Cl 4 is formed. 

3. When the free base is warmed with methyl iodide, an addi- 
tion product C5H5N.CH3I is formed. When this is warmed with 
solid KOH, it gives a very pungent disagreeable odor. This is a 
delicate test for pyridine. 

Coniine is propyl piperidine and is the alkaloid of conium 
maculatum 



CH2CH2CH; 



NH 

It is still more toxic than piperidine and is the cause of the poison- 
ing of cattle which have eaten the plant or in some cases, browsed 



252 



CHEMICAL PHARMACOLOGY 



on the roots, or drunk water contaminated with the alkaloid. 
The drug raises blood pressure by a local action on the peripheral 
vessels and slows the heart rate by central vagus stimulation. 
In fatal cases death is due to paralysis of the nerves to the respira- 
tory muscles. Chemically it is one of the simplest known alka- 
loids, one of the few liquid alkaloids, and closely resembles nicotine 
in composition and action. 

The substance is a colorless oil, boils at 167°C and like nicotine 
is readily soluble in water, to which it imparts an alkaline reaction 
(note the solubility in water) . It has a peculiar mouse-like odor. 
As a rule free alkaloids are rather insoluble in water. Coniine 
was formerly much used, but at present is not used in medicine. 
It is excreted in the urine. 

Tests 

1. It gives the pyridine tests p. 251. 

2. Test the solubility in water and note reaction and odor. 

3. Place a drop of coniine on a watch crystal. Add 2 drops of 
concentrated HC1 and evaporate to dryness on a water bath. 
Needle like or columnar yellow crystals of coniine hydrochloride 
frequently in star shaped clusters are deposited. They are 
doubly refractive. 

4. Dissolved in concentrated HN0 3 or H 2 S0 4 the crystals are 
not colored. 

5. The alkaloidal reactions especially delicate for coniine are 
— iodopotassium iodide (1 :8000) ; phosphomolybdic acid (1 :5000) ; 
potassium mercuric iodide (1:8000). 

Nicotine, is a more complicated alkaloid than coniine and is 
probably a pyridyl-/?, tetrahydro-N methjd pyrrole and may be 
represented by 

N-CH 3 



HC 



CH 2 - 



CH< 



CH< 



N 



NICOTINE 



253 



It is a colorless liquid, oily, with a pungent characteristic odor, 
boils at 241°C, and rapidly turns brown on exposure to the air. 
The drug is very toxic and raises blood pressure much like ad- 
renaline but by an action on the peripheral ganglion cells, while 
adrenaline acts on the sympathetic endings. Nicotine also resem- 
bles coniine in action. Death results from a stimulation and 
paralysis of the central nervous system. 

On standing, due to partial oxidation, a double-bonded com- 
pound (nicoteine) may be formed which is more toxic than nico- 
tine. 

CH 3 




CH 



CH 



N 



CH, 
NH 



On further oxidation oxynicotine 




— CH 



CH, 



CHO 



CH : 



NH.CH 3 

CH \CH 2 anc * metanicotine, 



CH 



CH ; 



N 



much less toxic derivatives, are developed. 



254 CHEMICAL PHARMACOLOGY 

When nicotine is oxidized with chromic or nitric acid, or po- 
tassium permanganate, /3. pyridine carboxylic acid is formed. 

COOH (nicotinic acid) 






N 

This shows that nicotine is a pyridine derivative with the side 
chain in the fi. position. 

The blood pressure raising action of nicotine is very great, 
small doses injected into the circulation will raise the pressure 
as much as adrenaline. There is however, quick paralysis of the 
nervous system and a second dose may have no action, or even 
cause a fall of pressure or death of the animal. This blood pres- 
sure raising seems to be due to the pyrrolidine moiety and not to 
the pyridine ring since the action is not shown by pyridine or 
nicotininc acid, but is produced by piperidine, pyrrolidine and 
N, methyl pyrrolidine. 

Nicotine occurs in plants in combination with malic and tartaric 
acids. At least three other alkaloids also occur in tobacco. 
These are nicotimine, nicoteine and nicotelline. The natural 
nicotine is levo-rotatory, synthetic nicotine like most synthetic 
products, is racemic. This synthetic product has been sep- 
arated by Pictet from the tartrate into the optical antipodes, 
and the levo-form corresponded in every way to the natural prod- 
uct. The lethal dose of 1. nicotine for guinea pigs, is only one- 
half that of the dextro-form, and the toxic symptoms are different 
from the dextro (Mayer Verichte, 1905, 38, p. 597). 

Nicotine is extremely poisonous. Four milligrams (about 
1/10 drop) in man have produced severe toxic symptoms mani- 
fested by giddiness, ringing in the ears, disturbance of respiration, 
sleeplessness and tetanic spasms. One drop on the tongue of 
a small cat will cause death in a few minutes. It is absorbed from 
the tongue, eye, or rectum very rapidly. The harmful effects of 
tobacco are due to its action on the nervous system, heart and 
digestive apparatus. The other rather unknown alkaloids of 
nicotine perhaps also play a role. 



NICOTINE 



255 



The end products of oxidation are not well known because of 
the small fatal dose, but when minute amounts, are inhaled, as 
in case of smoking it is probably completely oxidized, though 
after toxic doses some excretion takes place by the lungs and 
kidneys. 

NICOTINIC ACID 



The a, /?, and y mono carboxylic acids of pyridine, are known 



as 



COOH 



COOH 



COOH 



N 
Picolinic acid 



N 
Nicotinic acid 



N 
Isonicotinic acid 



These can be obtained by oxidation of the corresponding ethyl 
derivatives of pyridine. Their chief interest in pharmacology 
lies in the fact which Funk has suggested that a mother sub- 
stance of nicotinic acid is the vitamine of rice and is removed by 
polishing. Nicotinic acid has been found in the unpurified 
product, but the pure acid is inactive in the treatment of 
beri beri. 

TESTS FOR NICOTINE 

1. It gives the pyridine tests page 251. 

2. When a drop of nicotine and a few drops of cone. HC1 are 
evaporated slowly in a watch glass, on a water bath it remains 
amorphorus. No crystals, or only a suspicion of crystallization, 
occur when the mixture is kept in a desiccator over sulphuric 
acid. It differs in this respect from coniine. 

3. Roussin's Test. — Dissolve a drop of nicotine in 5 cc. of dry 
ether in a test tube. Add an equal volume of ether containing 
iodine in solution. Stopper, shake and set aside — in time ruby 
red crystals — Roussin's crystals — appear. Old resinous nicotine 
may not give this test until after redistillation. 



256 CHEMICAL PHARMACOLOGY 

4. Schindelmeiser's Test. — Fresh nicotine with one drop of 
formaldehyde free from formic acid, and one drop of concen- 
trated sulphuric acid gives a rose red color. If too much formal- 
dehyde is used a green color results. 

5. Physiological Tests. — Nicotine first stimulates then paraly- 
zes all autonomic ganglion cells. When injected into an animal, 
the heart and respiration are first stimulated, but are paralyzed 
by larger doses. The blood pressure is raised enormously by 
the first dose— later the drug is inactive because of paralysis of 
the ganglion cells. 

STRYCHNINE 

The chemistry of strychnine is not understood. Perkin and 
Robinson (Jour. Chem. Society, 1910, 305) have suggested as a 
tentative formula 

CH 2 CH 






CH CH 

CH CH 2 

N C CH CH 2 

CO N— CH CH 2 

V \/ 
CH CH 

I 
OH 

Strychnine 

From a therapeutic point of view the effect of strychnine is 

perhaps over estimated. Toxic doses have a pronounced action, 

but the actions after therapeutic doses are mild. Respiration is 

accelerated, the heart rate is slowed, vasomotor tone is increased, 

due to an action on the central nervous system. Brucine has a 

similar action but only J£o as strong. Thebaine, one of the opium 

alkaloids, has a similar action. 

The Fate of Strychnine 

The greater part of strychnine is excreted unchanged in the 
urine. A small amount is oxidized in the body. This oxidation 
has been shown indirectly by injecting strychnine into rabbits, 
whose kidneys were removed, thus preventing excretion. It was 



STRYCHNINE AND BRUCINE 



257 



found in this way that in small divided doses much more than the 
fatal dose can be given without causing spasms. The difference 
in the amount given and the amount excreted is hard to deter- 
mine accurately because of the small fatal dose. 
Tests for Strychnine and Brucine 

Bichromate Test. — Place a trace of strychnine on a white glass 
or tile dish. Add a drop of concentrated H 2 S0 4 , then a small 
crystal of potassium bichromate. Draw this crystal over the 
plate with a glass rod. An intense purple or violet color 
results, gradually becoming red, then yellow, or a blue-violet-red- 
orange-yellow play of colors, appears. This is a characteristic 
play of colors and is one of the most beautiful and delicate tests 
in chemistry. 

Physiologic Test. — One-tenth of a milligram injected into a 30 
gram frog will cause a characteristic tetanus in about 10 
minutes. 

Brucine. — This alkaloid occurs in nux vomica with strychnine : 

J.. To a little powdered nux vomica, add a few drops of con- 
centrated HN0 3 . The orange color is due to brucine. 

2. To a small portion of brucine in a test tube add a drop of 
HNO3. A blood red color which turns yellow on heating is the 
result. It turns to violet when a few drops of sodium thio- 
sulphate (hyposulphite), Na 2 S 2 3 , stannous chloride or colorless 
ammonium sulphide are added. Excess of HN0 3 must be 
avoided. The violet color changes to green when NaOH is 
added. These changes are given only by brucine. 

Arecoline, C 8 Hi 3 N0 2 , is the chief alkaloid of the nut arecoline 
catechu, and occurs together with arecaine, arecaidine and guva- 
cine. It is a colorless volatile oily liquid which boils at about 
220°C. Arecoline is the methyl ester of arecaidine. 
CH CH 



H 2 C 



H 2 C 



C.COOH H 2 C 



CH, 



H 2 C 



C.COOCH; 



CIL 



N.CH 3 

Arecaidine 



N.CH 3 

Arecoline 



17 



258 



CHEMICAL PHARMACOLOGY 



Arecoline has been prepared synthetically by Wohl and John- 
son (Berichte, 1907, 40, p. 4712) commencing with acrolein. 
The synthesis is complex. 

Arecoline and its salts are highly toxic and resemble nicotine 
and pilocarpine in action, while arecaidine is non-toxic. They 
act on the nerve endings of the para sympathetic system causing 
a marked flow of saliva. It also resembles nicotine in action and 
it may be said from its action to be a combination of nicotine and 
pilocarpine. Large doses may cause convulsions which soon 
pass into paralysis. Some European pharmacopoeias recognize 
arecoline as a sialogogue and diaphoretic. 

Little is known regarding the fate of these alkaloids in the body. 

Quinoline — Quinoline is a colorless oil having a specific gravity 
of 1.095 at 20°C. and boiling at 239°. It occurs together with 
isoquinoline, in coal tar and bone oil. It may be considered as 
a condensation of benzene and pyridine rings. 




N Isoquinoline 

Both are found in coal tar and bone oil distillates. They are hard 
to separate pure and are, therefore, made synthetically. The 
formation of quinoline from aniline and allyl aldehyde proves its 
formula : 



+ OHC-CH :CH< 




O = 




+H 2 



QUININE 



259 



Quinoline Alkaloids. — The important representatives under 
this head are the strychnine and quinine alkaloids. Quinoline 
itself has antiseptic and antipyretic properties. Compared with 
quinine it is, however, feebly antipyretic. The structure of 
quinine has not yet been confirmed, but is represented by: 



CH 5 



CHOH— CH- 




-OCHc 



CH 



CH 2 CH— CH = CH 2 

I I • 
CH2 CH2 

\/ 

-N 



Quinine 



N 



Action 



Quinine is toxic to all kinds of protoplasm, but has a specific 
or selective toxic action on undifferentiated protoplasm such as 
white cells and malarial plasmodia. Its use in medicine is due 
to this action. It reduces heat formation by an action on the 
cells where heat is generated, though it to some extent increases 
heat loss. This antipyretic action is, however, small in amount. 
The action of quinine is thought to be due mainly to the piperi- 
dine ring portion of it, which Frankel has called the "Loiponic 
acid portion." The vinyl side chain on this ring is not considered 
important in its action. 

The Fate of Quinine in the Body 

70 to 75 per cent, of it is oxidized and disappears. The re- 
mainder is excreted in the urine, only traces being found in 
the feces. No tolerance for it is gained by the body, and the 
rate of oxidation remains the same after prolonged usage. 



260 



CHEMICAL PHARMACOLOGY 



Schmitz (Schmidebergs Arch., 1907, 56, 301) gives the following 
experiments to show the excretion of quinine: 

Exp. I. 0.817 g. quinine given, 0.217 g. recovered — 26.6 per cent. 
Exp. II. 0.817 g. quinine given, 0.244 g. recovered — 29.9 per cent. 
Exp. III. 1 . 226 g. quinine given, . 346 g. recovered — 29 . 7 per cent. 

When given subcutaneously the excretion is slower. 



Day 


Quinine given 
daily 


24-hour 
urine, cc. 


Quinine 
recovered 


Per 
cent. 


Second 


0.605 


1400 
1700 
1400 
1450 
1600 
1500 


0.108 
0.120 
0.083 
0.128 
0.076 
0.071 


17 9 


Third 


19 8 


Fourth 


13.7 


Fifth 


21.1 


Sixth 


12.6 


Seventh 


11.7 



ASSAY OF THE ALKALOIDS IN CINCHONA BARK 

The Calisaya bark is most easily worked and is .crystallized 
most readily by the Keller-Haubensack method: Put 12 grams 
of calisaya bark in fine powder in a flask and add 120 grams of 
ether. Shake thoroughly and add 10 cc. ammonia hydroxide — 
10 per cent. NH 3 . Shake frequently during 30 minutes. Then 
add 15 cc. water and shake thoroughly. Pour 100 grams of the 
clear ether extract into another flask and add 40 cc. of 1 per cent, 
sulphuric acid. Shake thoroughly and allow to settle. The acid 
aqueous solution contains the alkaloidal sulphates. Pour off 
most of the ether without losing any of the water solution. 
Transfer the acid solution to a separatory funnel and make alka- 
line with ammonium hydroxide (6 cc. 10 per cent, solution). 
Extract with a mixture of 34 ether and % chloroform, using about 
40 cc. of the mixture. Separate this extract and transfer it to a 
dry flask. Repeat the extraction with 20 cc. of the ether chloro- 
form mixture. Separate and transfer this also to the flask con- 
taining the first extract. To get rid of the water filter through a 
dry filter into a weighed dry flask and allow to evaporate. The 



ISOQUINOLINE 



261 



alkaloids will crystallize out. After the solvent has evaporated, 
weigh and calculate the percentage of alkaloids in the bark. 

Tests for Quinine 

A solution of quinine in sulphur, acetic or tartaric acids shows 
a beautiful light blue fluorescence. The addition of a small 
amount of these acids increases the fluorescence. Solutions of 
the alkaloid in hydrochloric or hydrobromic acids are not 
fluorescent. Salts diminish it. The fluorescence is best seen by 
drawing the solution into a pipette. 

Thalleioquine Test. — (Thallos — green) . To 10 cc. of a solution 
of quinine bisulphate add a few drops of freshly prepared chlo- 
rine or bromine water and an excess of ammonia. Stir. A 
characteristic emerald green color develops. Urea, antipyrine 
and caffeine, interfere with this test. Morphine, pilocarpine, 
cocaine, atropine, codeine, strychnine, phenol, and chloral have 
no influence. It is very important that the chlorine or bromine 
water be freshly prepared as the presence of HC1 or HBr may 
prevent the development of the color. 

Isoquinoline Alkaloids. — The most important are papaverine, 
hydrastine, narcotine, cotarnine, and berberine. 

The formula of none of these is definitely established. Skele- 
ton f ormulae for papaverine and berberine are : 




— O.CH3 



\O.CH 3 
Papaverine 



262 



CHEMICAL PHARMACOLOGY 



CH ; 



0- 



0- 




'— O.CH; 



\O.CH 3 
Berberine 

They are of little importance in medicine and their fate in the 
body is not well known. 

Hydrastine and Hydrastinine. — These are isoquinoline alka- 
loids prepared from the root of hydrastis canadensis. On decom- 
position, hydrastine takes up water and hydrastinine and opianic 
acid are produced: 

C 21 H 21 N0 6 + H 2 = C 10 H 10 O 5 + CnHuN, 
Hydrastine Opianic acid Hydrastinine 

CHO 



Opianic acid has the formula: 



COOH 
OCH3 



OCH; 



Formulas assigned to hydrastinine and hydrastine are: 



HYDRASTINE 



263 



CH 2 






0— 



•o- 



CHO 
/%/ NH.CH 3 

I 
CH 2 



CH 3 0- 



OCH3 



CH 5 



Hydrastinine 



CO, 



-CH' 



CH 



:0 



CH< 



.0— 



O- 



N.CH ; 
CH 2 



C.OH2 
Hydrastine 

Narcotine, an opium alkaloid, is methoxy hydrastinine and 
yields opianic acid on hydrolysis. Hydrastinine has been synthe- 
tized by Fritsch and its synthesis throws light on the structure of 
Irydrastinine. Hydrastinine increases the reflex irritability of 
frogs leading to tetanus resembling that produced by strychnine, 
and finally to paralysis. In mammals the small amounts slow 
the pulse; larger doses cause convulsions and tetanus. The 
pulse is slowed by stimulation of the vagus center, and blood 
pressure rises for the same reason. It also causes contraction of 
the uterus. It is excreted unchanged in the urine. 

Hydrastinine. — The hydrolysis of hydrastine changes its action 
markedly. Hydrastinine causes but a small increase in blood 
pressure. It has no convulsant action but instead is a central 
depressant and does not weaken the heart, but stimulates it by 
direct action. Its most important action is on the uterus — due to 
a direct action on the muscle though there is some action through 
the nerves. 

Hydrastine Tests 

1. Concentrated sulphuric acid dissolves hydrastine without 
color until warmed when the solution becomes violet. 

2. When dissolved in dilute sulphuric acid, and very dilute 
potassium permanganate added, drop by drop, hydrastine is 
converted into hydrastinine, and. the solution shows a beautiful 
blue fluorescence. 

3. Froehde's reagent dissolves hydrastine with a rose red 
changing to brown color. 



264 



CHEMICAL PHARMACOLOGY 



4. Soluble chromates precipitate insoluble hydrastine chromate 
which gives a fleeting red color with sulphuric acid. 

HYDRASTININE 

1. It crystallizes from light petroleum in colorless glancing 
needles which melt at 116°-117°C. 

2. It is optically active. 

3. It is soluble in alcohol, sparingly soluble in water, forming 
yellow fluorescent solutions. 

4. It forms salts with hydrochloric acid — which is the form of 
the alkaloid used in medicine. The aqueous solutions show a 
blue fluorescence. Bromine water gives a yellow precipitate. 

Narcotine. — Narcotine is an opium alkaloid; in composition 
it is methoxy-hydrastine. It crystallizes from alcohol in color- 
less needles which melt at 176°C. When hydrolyzed with dilute 
acids it yields opianic acid and hydro-cotarnine. 

1. C 22 H 23 N0 7 + H 2 = C 10 H 10 O 5 + Ci 2 H 15 N0 3 
Narcotine Opianic acid Hydro-cotarnine. 

2. With dilute HN0 3 narcotine gives opianic acid and co- 
tarnine the constitution of which are 



OCH 3 

I 
C 

•\ 

HC C.OCH- 



CH.,0- 



H 
C 

•\ 

-C CH 



HC C.CO 



H 2 C.O< 



C 

I 
HC— O 

CH3O.C CH 

S\/\ 

/O— C C N.CH 3 



0— C C CH, 



C C 
H H 2 

Narcotine 



CH3O— C C— C = 

V H 

C 

I 
HO— C=0 



Opianic acid 







NARCOTINE 265 

CH3O 

I H 2 
C C 



y O— C C N— CH ; 

H 2 < I || I 
x O— C C CH 2 



C C 
H H 2 

Hydro-cotarnine 

In action narcotine resembles morphine but is less hypnotic 
and has some strychnine-like action though the hypnotic action 
predominates (see page 256). Mohr states that in cats con- 
vulsions precede the narcotic stage. It is but little used in thera- 
peutics, although it has some antipyretic action. 

Tests for Narcotine 

1. The alkaloid dissolves in concentrated sulphuric acid with 
a greenish color changing to reddish violet and after several days 
to a raspberry red. 

2. When narcotine is dissolved in concentrated sulphuric acid 
and a trace of nitric acid added a red color is produced. 

3. A solution of narcotine in sulphuric acid gives a blue color 
on warming with gallic acid (Labat) . 

Cocaine is the alkaloid of coca leaves. It is a white crystal- 
line solid that melts at 98°C. The hydrochloride is the most 
important salt. The formula of cocaine is. 

H 2 C CH HC— COOCHs 

I I 

N— CH 3 CH— OOC— C 6 H 5 

I I 

H 2 C CH CH 2 

Cocaine or methyl benzoyl ecgonine 

On hydrolysis cocaine gives methyl alcohol, benzoic acid and 
ecgonine : 



266 CHEMICAL PHARMACOLOGY 

CH 2 



CH S 



CH 


CH.COOH 


1 
N.CH 3 

1 


N OH 


CH 


— CH 2 



Ecgonine 



Cocaine can be prepared from ecgonine by benzoylation and 
methylation; and ecgonine has been synthetically prepared from 
tropine, but so far the synthetic product has not been separated 
into its optical isomers. The natural product like most natural 
alkaloids is levorotatory. A dextrotatory (isococaine) isomeride 
of 1. cocaine has been prepared from coca leaves, but this is now- 
thought to be formed from the 1. cocaine by the action of alkalies. 
L. cinnamyl cocaine C19H23O4N is the chief alkaloid of the 
Java cocoa leaves. The d. isomeride does not occur in the coca 
leaves but has been prepared synthetically. 

Action of Cocaine 

The chief action of cocaine is its local anesthetic effect. This 
is due to its general protoplasm action, though it acts more 
strongly on the sensory nerves than on motor ends. The effect 
is due to the benzoyl group. Large doses first stimulate, then 
paralyze the central nervous system, chiefly in a descending di- 
rection. The heart muscle is directly stimulated by small doses 
and paralyzed by larger doses. The striated muscles are also 
stimulated by a direct action. There is a marked mydriasis, 
formerly thought to be due to stimulation of the sympathetics 
locally, but later work questions this location. The toxic dose 
of cocaine varies enormously. Swabbing the tonsils with 4 
per cent, has proved fatal in some cases while over 1.5 grams have 
been taken per os with recovery. 

The Fate of Cocaine in the Body 

Neither man nor dog eliminates in the urine more than 5 per 
cent, of the cocaine ingested, and since the urine contains no 
ecgonine it is thought to be profoundly changed in the organism. 
In the oxidation in the body it is thought to be first decomposed 
into ecgonine, benzoic acid and methyl alcohol, and these are 



NARCOTINE 267 

then oxidized. Proells could not detect cocaine in cadaveric 
material after 14 days. 

ARTIFICIAL COCAINES 

A large number of artificial cocaines have been prepared. All 
these contain a benzoyl radical. The most important artificial 
cocaines are : 

Anesthesine, or para amino ethyl benzoic acid : 




NH 2 < V-CO.O C 2 H 



'2-L-L5 



Pro-cocaine or novocaine is the hydrochloride of the diethylamine 
derivative of anesthesine or para amino benzoyl di-ethyl amino 
ethanol and has the formula. 



NH < >CO.O.CH 2 CH 2 N(C 2 H 5 ) 2 HCl 



A number of other substitutes have been prepared. 

Tests for Cocaine 

1. Heat a few milligrams of cocaine with a few drops of alco- 
hol and concentrated H 2 S0 4 . Note the odor of ethyl benzoate. 

C 6 H 5 COOH + C 2 H 5 OH = C 6 H 5 COOC 2 H 5 + H 2 

2. Boil a solution of cocaine with a drop of H 2 S0 4 and add a 
drop of Fe 2 Cl 6 . Ferric benzoate is precipitated. 

3. Physiological tests: Local anesthesia and dilation of the 
pupil, when applied locally. 

THE PYRROL OR PYRROLIDINE GROUP OF ALKALOIDS 

1. This includes, in addition to pyrrol and pyrrolidine, hygrine, 
a derivative of n. methyl pyrrolidine : 

CH 2 .CH CO.CH 2 .CH 3 

^>N.CH 3 

CH 2 CH 2 

and kuskhygrine from the leaves of erythroxylon coca. 



268 



CHEMICAL PHARMACOLOGY 



2. Stachydrine from stachys tuberifera has the formula. 
CH2 — — CH2 



CO CH 



0- 



CH< 



-N (CH,): 



which is a dimethyl betaine of pyrrolidine. 

The atropine and cocaine group of alkaloids may be considered 
in this group or in the tropane group. They may be regarded 
as a combination of a piperidine and a pyrrolidine nucleus, which 
is tropane 

CH.2 CH — — — CH2 




CH 



Tropane 
Pyrrol — (pyros, fire-ol., oil) is a constituent of coal tar, and a 
product of the distillation of bones. It has the formula: C4H6N 
or 

CH CH 



CH 



CH 



NH 

It is more toxic than pyridine or piperidine. It resembles 
benzene in action. 

Blood coloring matter, chlorophyll and protein decomposition 
products contain a pyrrol nucleus. The derivatives of pyrrol arc 
classified according to the scheme 

4— —3 /S 7 — j8 



or 



1 /2 

\/ 

NH 



Nil 



NAKCOTINE 269 

On reduction with hydriodic acid and phosphorus, pyrrol 
yields pyrrolidine: 

CH 2 CH.2 

I ! 

CH2 CH2 



NH 

which is a much stronger base than pyrrol. 

Pyrrol has been synthesized in several ways. It has been 
formed by the interaction of succin-dialdehy de and ammonia : 

CH 2 — C/ + NH 3 CH 2 .CH( 

X X NH 2 

y H . .NH 2 

CH 2 — C^ + NH 3 CH 2 .CH<^ 

X X 0H . 

CH = CH X 

)>NH + NH 3 + 2H 2 
CH = CW 

Pyrrolidine has also been formed by heating penta-methylene 
diamine with hydrochloric acid. 

H H 2 v 

X C CH 2 

. : + hci -> I I 

H 2 C CH 2 + NH4CI 



y CH 2 CH 2 NH 
CH 2 < 



CH, 



NH 

Pictet (Ber. deut. chem. Gesells, 1907, 40, 3771) thinks that alka- 
loids in plants are formed by the breaking down of complex nitro- 
genous substances, such as protein and chlorophyll, and by a 
condensation of these substances with others, as in the syntheses 
above. He is of the opinion that methylation within the plant 
can be accomplished by the action of formaldehyde on amino or 
hydroxyl groups : 

ROH + CH 2 = RO CH 3 + 
or RNH 2 + CH 2 = RNHCH 3 + 



270 



CHEMICAL PHARMACOLOGY 



It should be noted that methylation in the animal body is of rare 
occurrence (see p. 249). Various alkaloids may then be formed 
by other changes, for example, by heat. The secretion of alka- 
loids by plants may, according to Pictet, be a means of getting 
rid of nitrogen which cannot be used in metabolism. It is a 
curious fact that these alkaloids, though highly toxic to animals, 
are not toxic to the plants themselves. The theory that alkaloids 
are necessary compounds in the plant and are secreted to protect 
the plant from animals does not agree with the fact that plants 
grow just as well when moved into other latitudes, yet the content 
of alkaloid is much diminished. 

Methyl pyrrol can be changed to pyridine by heat : 



\ / 



N.CH 3 N Pyridine. 

Fate of Pyrrol in the Body 
Pyrrol and its derivatives appear to be easily destroyed in the 



body. 



TROPINE ALKALOIDS WITH DIHETERO CYCLIC NUCLEI 
Tropane Alkaloid. — Tropane has the formula : 
CH2 CH CH2 



NCH, 



CPL 



CH : 



-CH- 



/ 
CH 2 



This substance contains a piperidine ring and a pyrrolidine 
ring, consequently there may be some duplication in the classi- 
fication. The tropane alkaloids would include: 

I. The atropine group — atropine, hyoscine, hyoscyamine. 
II. The cocaine alkaloids — cocaine and tropo cocaine. 
III. The pomegranate alkaloids — pelletierine, isopelletierine, 
etc., from punica granatum. 



ATEOPINE 271 

IV. Cytisine from cytisus laburnum, lupinine from lupinus- 
luteus and niger, etc. 

Tropine differs from tropane in that one of the H. ions of tro- 
pane is replaced by hydroxyl : 

H 2 C — CH— — CH 2 

| | .CHsOH 

NCH 3 CHOH + C 6 H 5 .CH( 

| | X COOH 

H2C CH — — ■ — ■ — CH2 

Tropine Tropic acid 

Atropine is a combination of tropic acid and tropine. When 
other acids are used tropeines are formed. 

Atropine : 



CHo CH 0x12 

TT 

/ 



H XH2OH 



N.CH 3 (X /COCH; 

I . I \/ X C 6 H 5 

CH2 — — CH ■ CH2 

The main actions of atropine are stimulation of the central nerv- 
ous system and paralysis of the peripheral para sympathetic 
nerve endings. In these actions the tropine part of the ester 
is the more important. This is proved by the fact that other 
acids may be substituted for tropic acid. The only other acid 
that has jdelded an ester of practical importance is mandelic 
acid, which is 

Homatropine, C 5 H 7 N(CN 3 )C2H 4 O.CO.CHOH.C 6 H5 

The action of homatropine is practically the same as atropine 
but it is less toxic. It is used especially in eye work, since the 
dilation of the pupil caused by it lasts only a few hours, 
while that caused by atropine may last for days. 

The tropines derived from benzoic and cinnamic acids exert 
no mydriatic action. 

The Fate of Atropine in the Body 

Atropine is readily absorbed and excreted. After adminis- 
tration it has been found in most all tissues and fluids. It has 



272 CHEMICAL PHARMACOLOGY 

been found in the milk and in the foetal blood. It is decomposed 
to tropine and oxidized in the body, though some may escape 
unchanged in the urine. It is very resistant to putrefaction and 
has been found in bodies after two years. 

Tests for Atropine 

1. Boil a small amount with dilute H 2 S0 4 . This gives an 
orange flower odor which changes to that of bitter almond. The 
solution gives a green color when a trace of potassium bichro- 
mate is added. 

2. To a trace of atropine in a test tube add 10 drops of H?S0 4 
and heat until it becomes brown or until white fumes appear. 
Then add 2 volumes of water. During the heating there will be 
a sweetish odor resembling tuberose, which is characteristic 
(Gulichno). The odor is strengthened by adding a little KMn0 4 
(Reuss). This test is sensitive to 10 milligrams. 

3. Vitali'sTest. — Put 1 or 2 mgms. of atropine in an evaporating 
dish and dissolve in it a few drops of fuming nitric acid and 
evaporate to dryness high above the flame or on a water bath; 
cool and touch the spot with a drop of alcoholic solution 
of KOH. The color will be violet, changing to cherry red. Vera- 
trine also gives this test, hence it is characteristic only in the ab- 
sence of veratrine. 

4. Atropine dilates the pupil and gives a dry sensation to the 
mouth and eliminates vagus action on the heart, thus causing a 
very rapid rate of heart. These tests can be recognized with 
certainty in presence of veratrine. 

Scopolamine or Hyoscine, C 17 H 2 i0 4 N, is a tropane alkaloid 
whose composition is so closely allied to atropine and hyoscya- 
mine that the same reactions are given. With mercuric chloride 
atropine gives a yellowish red precipitate of mercuric oxide, 
while hyoscyamine gives a white precipitate. 

When warmed with barium hydroxide, scopolamine is hydro- 
lyzed yielding tropic acid and a base C 2 Hi 3 2 N — named 
pseudo-atropine, oscine, oxytropine or scopoline. 

Hyoscine resembles atropine in its action on the nerve termi- 
nals, but has practically no action in stimulating the central 
nervous system. The main action is a feeling of fatigue and 
drowsiness. It has been often used to produce "twilight sleep." 



GLYOXALINE 273 

THE GLYOXALINE GROUP OF ALKALOIDS 

This includes pilocarpine, isopilocarpine and jaborine, which 
may be a mixture of pilocarpine and isopilocarpine. There are 
other unimportant members such as pilocarpidine. The only 
one of interest in medicine is pilocarpine. 

Glyoxaline is metameric with pyrazole and may be regarded 
as a pyrrol nucleus in which one methine radical has been replaced 
by nitrogen. It is formed when ammonia acts on glyoxal in 
presence of formaldehyde; sufficient formaldehyde may be 
formed from the glyoxal without the extra addition of it. 
CHO NH 3 CH— N . 

| + +0:CH 2 -+|| ^CH + 3H 2 

CHO NH 3 CH— NH X 

Glyoxaline 
The purine group of alkaloids contain a glyoxaline nucleus and 
may be regarded as a glyoxaline ring condensed with pyrimidine. 
2 CH — N 1 

^ \ 

3 N CH 6 

\ / 

4 C=C 5 

I I 

9 N NH 7 

^ CH / 
8 
Grlyoxaline may also be prepared by oxidizing benzimidazole 
with permanganate. 



— N . H COOH.C— N ^ 

^>CH-> || ^CH-> 

— NH X H COOH.C— NET 

Glyoxaline dicarboxylic acid 

H. C-N . 

|! ^CH + 2C0 2 

H. C— NH X 

Glyoxaline 
Compare with the given formula for purine, p. 283. 

18 



274 CHEMICAL PHARMACOLOGY 

Pilocarpine is a colorless oil, freely soluble in water, alcohol and 
chloroform and but slightly soluble in ether and light petroleum. 
It readily forms crystalline salts with acids and the nitrate is the 
most important. It is readily soluble in water. The alkaloid of 
commerce is derived from the leaves of pilocarpus jaborandi, a 
South American plant. It has been prepared synthetically, and 
based on this synthesis Jowett and Pinner consider pilocarpine 

C 2 H 5 — CH— CH— CH 2 — C N— CH 3 

to have the formula 

CO CH 2 CH CH 



N 

Iso-pilocarpine is probably a stereoisomeride. 
Action of Pilocarpine 

Pilocarpine is a strong stimulant to all glands, especially the 
sweat, salivary, bronchial, lachrymal, gastric, and intestinal. 
The smooth muscles of the alimentary tract, the urinary bladder, 
spleen and bronchi* are stimulated . The muscles of the blood 
vessels are not influenced, but when given intravenously the 
heart is slowed by an action on the vagus endings. When taken 
by mouth, the heart rate may be increased. This action has not 
been satisfactorily explained; it may be secondary. There is 
some stimulation of the central nervous system, followed by 
paralysis after large doses. The whole action of pilocarpine 
resembles that of muscarine, but it is much less poisonous. 

Pilocarpine is used in medicine almost totally for its diaphoretic 
action, especially in cases of dropsy and similar diseases. Iso- 
pilocarpine and pilocarpine have a similar but weaker action. 
Pilocarpic acid is inactive. Very large or toxic doses of pilocar- 
pine cause profuse sweating, flow of nasal secretion, tears, pallor, 
slow heart, and arrythmias, vomiting, diarrhoea, contracted 
pupil, tremors, cloudiness of the cornea, tracheal rales, and edema 
of the lungs. The part played by the glyoxaline ring has not 
been determined. 

Atropine is antidotal in all cases and a small dose will neutralize 
the effects of a large dose of pilocarpine. 



PHENANTHRENE GROUP 275 

Fate in the Body 

A large part is excreted unchanged in the urine. There may 
be some in combination (Curci). 

Tests for Pilocarpine 

1. The general alkaloidal reagents especially delicate for 
pilocarpine are iodo-potassium-iodide, phosphomolybdic acid, and 
phospho tungstic acid. 

2. Pilocarpine nitrate melts at 176°-178°. 

3. A solution of pilocarpine in formalin sulphuric acid when 
warmed becomes yellow-brown-red. 

4. In a test tube add a crystal of potassium bichromate to 2 cc. 
chloroform with pilocarpine and 1 cc. hydrogen peroxide; shake. 
Depending on the amount of pilocarpine the chloroform is blue 
violet, dark or indigo blue. 

5. Physiological tests: These are constriction of the pupil, 
slowing of the heart, profuse sweating and an edematous con- 
dition of the lungs. 

PHENANTHRENE ALKALOIDS 

Phenanthrene is an isomer of anthracene and occurs with it in 
coal tar. 



Phenanthrene 




Phenanthraquinone 


4 3/ \2 

V \ • / 

\ / \ 
6 7 8 


> 

9 


CO CO 

/ \ 

/ \ / 

\ ■/ \ 



Phenanthrene Group.- — The most important representatives 
of the group are morphine, codeine, thebaine, and apomorphine. 
On distillation with zinc dust these alkaloids yield pyrrol, 
pyridine, quinoline, and phenanthrene; consequently, they may 
be placed under either of these headings. 

Phenanthraquinone is obtained from phenanthrene by oxida- 
tion with glacial acetic and chromic acids. According to Amoss, 
morphine is a derivative of tetrahydro-dioxy phenanthrene to 
which a, morpholine is added. To morpholine he assigned the 
formula- 



276 



CHEMICAL PHARMACOLOGY 



O 



CH 2 

CH 2 




CH 2 
CH 2 



and to morphine 
OH. 



OH 



/ 



C14H10 



CH 2 
CH 2 



NH 

Morpholine 

CH 2 

• \/ \ 

CH- 



N 

CH 3 
Morphine 



N— CH- 
CH 2 



CH 3 0\ /\ /\ 

\/ \/ \/ 

CH 
CH 2 



0- 



C 



CH< 



CH.OH 

Codeine (Knorr) 
CH 2 

• \/ \ 

CH — N— CH 3 



CH 3 0\ 



HO 
CH 2 HO 






x/ \y \/ 

CH / 
CH 2 
/ 

o- -c 

\ * 
\// 

COCH3 

Thebaine (Knorr) 



CH 2 CH 2 
Apomorphine 



N— CH 3 
CH 2 



CH 2 N— CH- 
CH CH 2 



CH ; 



CH 3 0\/\/'\/ 

C— H 

-C CH 2 



H C 

/\ 
H OH 

Codeine (Pschorr) 



THEBAINE 277 

CH 2 N— CH 3 
CH CH 2 

CH 2 

CH 3 0\/\/\/ 

C— H 

C CH 

H C 

I 
OCH 3 

Thebaine (Pschorr) 



Roser and Howard (Berichte, 1886, 19, 1596) think the re- 
lationship of morphine, codeine and thebaine may be shown as 
follows : 



HO, 



CH 3 



H 



(/ 



Ci 6 H 14 ONCH- 



\ 



CieHuONCHg 



OH 



Morphine 



Codeine 



CH3O, 



CH3O' 



:C 16 H 12 NO.CH, 



Thebaine 



In accordance with this view it has been found that the prin- 
cipal decomposition products of all three are similar. Codeine 
is methyl morphine. The graphic formulas are now known 
with certainty, but among others the following have been pro- 
posed for morphine : 



278 



CHEMICAL PHARMACOLOGY 

CH 2 



• 



HO 



CH N— CH 3 

I 
CH 2 



% /\ /x / 
x/ \y 



H 



0- 



CH ; 
CH 2 



CH 2 N— CH ; 
CH CH 2 

CH 2 

H0\/\/\/ . 
C— H 

C CH 2 

H C 



H OH 

Pschorr's formula 



H OH 

Knorr's later formula 



CH : 



/- 



/\ 



HO 



\ 



\/ 



O CH 2 - 

\/ 
H 



CH 
/% 

X 

CH / 

■N 



CH; 

CH CH 2 

\ / 
\/ 
C 



H OH 

Bucherer's formula modified by Knorr 



APOMORPHINE 279 

The principal pharmacological actions of morphine are: 

1. A marked depression of the central nervous system, com- 
mencing above and descending. The perception to pain and the 
sensitivity of the respiratory center, seem more depressed than 
other functions. 

2. Depression of the blood pressure and slowing of the heart 
due to an action on the medullary centers. 

3. A decrease in the peristalsis Of the alimentary canal, pre- 
ceded in some animals by stimulation. 

4. A marked constriction of the pupil, due apparently to the 
removal of a central action. The constriction disappears in the 
paralytic stage, and in some animals in which morphine causes 
stimulation or excitement rather than depression (cat, horse 
and others) the pupil is dilated at all stages. 

5. The cord is stimulated with all these drugs, and the reflexes 
exaggerated. Morphine applied directly to the cord will cause 
convulsions, and some of the morphine alkaloids stimulate only. 
Dixon (Manual of Pharmacology, 1906, p. 137) because of these 
differences arranges the morphine alkaloids as follows with the 
percent of these alkaloids in opium 

Morphine (most narcotic) 10. per cent. 

Papaverine 1.0 per cent. 

Codeine 0.5 per cent. 

Narcotine 6.0 per cent. 

Thebaine 0.3 per cent. 

Laudanine (most convulsant) trace 

Apomorphine.— When morphine is heated in a sealed tube with 
strong HC1 at 140°C. it loses a molecule of water and apomor- 
phine is formed. This change it has also been asserted, occurs 
when morphine salts or their solutions are exposed to light, but 
no proof of this has been advanced. 

Solutions of apomorphine have a green color and the entire 
physiological action of morphine is changed by the loss of water 
from the morphine molecule. 

Apocodeine. — C 18 Hi90 2 N has been prepared by the action of 
zinc chloride solution on codeine hydrochloride. It is supposed to 
bear the same relation to codeine that apomorphine does to 



280 CHEMICAL PHARMACOLOGY 

morphine. Dott (Pharm. Journal, 1891, III, XXI, 878, 916, 
955, 996) claims that it is not a pure compound, but a mixture 
of chlorocodeine apomorphine, amorphous bases, and codeine 
(Knorr and Raabe, ibid., 1908, 41, 3050). 
The chief actions of these apo-compounds are : 

1. Apomorphine causes vomiting by a strong stimulation of 
the vomiting center, and 

2. Also stimulates: the secretory centers for saliva, perspira- 
tion, etc. It has a paralytic action on skeletal and heart muscle. 

3. Apocodeine paralyzes all ganglion cells, and is toxic to all 
forms of motor nerve endings. 

The Fate of These Alkaloids in the Body 

Morphine is partly oxidized and a part is unchanged and ex- 
creted by the alimentary tract. This is a different method of 
excretion from most alkaloids which are excreted in the urine. 
Faust found that 70 per cent, of that administered to a non- 
immunized animal was excreted, but when tolerance is established 
the oxidizing power of the tissues is increased. The excretion 
into the alimentary tract begins soon after administration, as 
shown by the fact that morphine has been found in the vomitus 
soon after hypodermic administration. Codeine is excreted 
much in the same way as morphine but tolerance is harder to 
establish and more is excreted unoxidized. When injected 
intravenously Marquis found 15 per cent, of the morphine de- 
posited in the liver in 15 minutes and some retained in the central 
nervous system. A slight amount is excreted in the urine in 
combination with glycuronic acid. Morphine resists putrefac- 
tion and has been found in putrefying material after 15 months. 

Tests 

Apomorphine. — The solutions have a green color. 

1. To a dilute solution add a few drops of HC1 or H 2 S0 4 , then 
neutralize with Na 2 C0 3 and add a drop of an alcoholic solution 
of iodine. The emerald green color which is produced becomes 
violet when shaken with ether. 

2. Dissolve a trace of apomorphine hydrochloride in water and 
shake. A green color appears. Add a trace of ferrous sulphate 
and shake. The solution 'gradually turns blue and finally black. 



APOMORPHINE 281 

On the addition of alcohol the blue color returns (different from 
codeine and morphine). 

3. Dissolve a trace of apomorphine in concentrated H 2 S0 4 and 
add a drop of concentrated HN0 3 ; a violet color changing quickly 
to red and yellowish red is formed. 

4. Physiologic test: 0.01 gram apomorphine hydrochloride 
hypodermically in a dog causes vomiting in a few minutes. 

Codeine. — 1. To a little of the dry alkaloid in a crucible add a 
few drops of concentrated H 2 S0 4 and heat. A greenish color 
which changes to violet-red results. Morphine gives none, or 
only a slightly yellow color, except when heated, then it is brown. 
HN0 3 changes the reddish violet color of codeine to yellow and 
purple. 

2 Codeine with H 2 S0 4 heated, with a drop of nitric acid added, 
gives a blood red color. 

3. Codeine with H 2 S0 4 gives no color; add a drop of formalin 
and a violet color is produced. Morphine gives an intense purple. 

4. Codeine with H 2 S0 4 with a trace of ferric chloride added 
gives a violet blue color. 

Tests for Morphine 

1. 1 gram of morphine is soluble in 3340 cc. of water, 210 of 
alcohol, 6250 of ether, or 1220 of chloroform. 

2. A saturated aqueous solution of morphine is alkaline to 
litmus. 

3. Concentrated sulphuric acid produces either no color or 
only a red or yellow tint when added to a morphine solution. 
On heating a brown color is developed. Concentrated sulphuric 
acid containing 0.1 per cent, formalin gives a purple color. 

4. Concentrated nitric acid with morphine produces an orange 
red color fading to yellow. 

5. Ferric chloride added to a neutral solution of morphine, 
made by adding dilute H 2 S0 4 to morphine, produces a blue 
color. 

6. Iodic acid test: When morphine in dilute sulphuric, is 
shaken with a few drops of iodic acid and chloroform, iodine is 
liberated and dissolves in the chloroform producing a violet color. 
Other reducing substances may give this test. 

7. Prussian blue test: When morphine is added to a dilute 



282 CHEMICAL PHARMACOLOGY 

mixture of ferric chloride and potassium ferricyanide, a deep blue 
color appears. When considerable morphine is added a precipi- 
tate may be produced. 

8. When morphine is added to silver nitrate with an excess of 
ammonium hydroxide a gray precipitate of metallic silver is 
formed. 

Thebaine. — 1. Thebaine gives a blood red coloration which 
gradually becomes yellowish red with concentrated sulphuric 
acid. 

2. With nitric acid thebaine gives a yellow color. 

3. Chlorine water dissolves thebaine. If ammonia be added 
to the solution it becomes red-brown. 

Papaverine occurs in opium to the extent of 0.5-1 per cent. 

H H 



H 3 CO— C C CH 



H a CO— C C N 
H 



\/\y 



CH 2 

A 

HC CH 

I II 

HC CO.CH 3 

V 

I 

OCH 3 

Papaverine 

It crystallizes in colorless poisons which melt at 147°C. It is 
insoluble in water, soluble in ether 1 to 260 and freely soluble in 
chloroform. Ether partially extracts it from tartaric acid solu- 
tion, and completely extracts it from alkaline solutions. Chloro- 
form extracts it easily from either acid or alkaline reaction. 



CAFFEINE 283 

Tests 

1. When pure, cold sulphuric acid does not color papaverine, 
it becomes violet when heated. Impure solutions may be violet 
without heating. 

2. Concentrated nitric acid dissolves papaverine with a dark 
red color. 

3. Papaverine gives a purple color, changing to black and 
green, when dissolved in sulphuric acid containing iodic acid. 

4. With iodine in alcohol, papaverine yields a characteristic 
crystalline periodide. 

THE CAFFEINE GROUP 

Caffeine and related drugs are important from the standpoints 
of biochemistry, pharmacology, and as foods. They occur 
especially in tea, coffee, cocoa, kola, gurana mate and in numerous 
other plants in small amounts. The most important drugs of 
this group are : 

Purine, or the nucleus of the group. 

Caffeine, or 1.3.7 — trimethyl xanthine. 

Theobromine, 3.7 — dimethyl xanthine. 

Theophylline, 1.3 — dimethyl xanthine. 

Xanthine, 2.6 — dioxy purine. 

Hypoxan thine 6— oxy purine. 

Guanine 2 — amino. 6 oxy purine. 

Adenine 6 amino purine. 

Uric acid 8 — hydroxy xanthine, or 2, 6, 8 trioxy purine. 

1 N = 6 CH 

I I 7 

2 CH 5 C NEL 8 

II II >H 

3 N 4 C -N " 

Purine 9 

The word purine is a portmanteau word, a combination of 

purum uricum. 

N(CH 3 )— CO NH —CO 

I I I I 
CO C— N(CH 3 ) X CO C N(CH 3 ) V 

I II ->H | || )CH 

N(CHs)— C W N(CH 3 )— N /X 

Caffeine Theobromine 



284 



CH— N— CO 

I I 
CO C— NH 



CHEMICAL PHARMACOLOGY 

i 

NH— CO 



CO C— NH, 



CH 3 — N— C 

Theophylline 

NH— CO 



-N 



/ 



CH 



HC C— NH, 



NH— C— N 
Xanthine 

NH— CO 
H 2 N— C C— NH. 



• 



CH 



II II A, 

N— C— N^ 
Hypoxanthine 

N=C— NH 2 



CH 



HC C-NR 

II II 
N— C— N 

Adenine 



/ 



CH 



N— C— N 
Guanine 

NH— CO 
CO C— NH, 
NH— C— NH 



> H 



/ 



CO 



Uric Acid 



Purine or the nucleus of the group is of interest only in showing 
the chemical relationship of the whole group to uric acid. Purine 
has been prepared from uric acid, and this in turn from simpler 
well known compounds. The sodium salt of uric acid when 
treated with phosphorus oxychloride, yields hydroxy di chlor 
purine. 

N=C— CI 



Cl.C C— NH, 



N— C— N 



/ 



C.OH 



When this is acted on by phosphorus trichloride, it gives trichlor- 
purine 

N^C.Cl 



Cl.C C— NH 



N— C— N 



\ 



C.C1 



CAFFEINE GKOUP 



285 



and when this is treated with hydriodic acid, diodo-purine is 
N^C.I 



I.C C— NH 



N— C— N 



\ 



CH 



formed, which when reduced by zinc dust and water gives purine 
(p. 283). 

According to Fischer purine may occur in the body, but can- 
not be detected on account of its ease of decomposition in the 
body. 

The establishment of the formulae of uric acid and related 
substances has been a slow growth. The suggestions for the 
synthesis came principally from a study of the products of 
hydrolysis of uric acid. Among these products were urea, para- 
banic acid, alloxan, allantoine, etc., depending on the oxidatizing 
agent. After numerous attempts, the following steps were 
successful in establishing the synthesis and formula of these 
bodies. 
(I) 



N 



H 



HO! CO NH— C 



/ 



O 



H 
+ 
H 



CO CH 2 + H 2 



N; 



iJHOiCO NH— CO 



!H 



(II) 



urea + malonic acid = malonyl urea or barbituric acid. 



/> 

NH— 'Cr HONjO 

C=OC|H 2 + 



NH— cr 

C C:N.OH 



NH— CO NH— CO 

Barbituric acid + Nitrous acid = iso-nitroso-malonyl urea 



286 CHEMICAL PHARMACOLOGY 

(III) Reduction of iso-nitroso NH Cr 

nialonyl urea gives: 

C CHNH 2 

NH CO 

amino barituric acid 

(IV) 

NH— Qf NH CT 

I ! I I 

C C H NH 2 + KCNO + HC1 = C CHNHCO 

NH C = NH C = ONH 2 

amino barbituric acid pseudo uric acid 

(V) Pseudo uric acid loses water on treatment with dilute 
mineral acids and gives uric acid. 

//° //° 

NH— CT NH CT 



C = CHNH. -> C = C NH 

I II \p — o \ 

| ^>CO + H 2 

NH C = :OH N NH C-NH 

pseudo uric acid uric acid or 2.6.8. trioxy 

purine 

By reduction, the purin base has been prepared from uric acid,, 
as shown above. 

Caffeine occurs especially in tea and coffee and similar stimu- 
lant food stuffs, in the following amounts : 

Tea 1-4 . 8 per cent. Kola nuts 2 . 5-3 . 6 per cent. 

Coffee . . . 1-1 . 5 per cent. Mate 1 . 2-2 . per cent. 

Gurana 3.0-5 per cent 

I I occurs partly free and partly combined as caffeine chlorogenate. 
Caffeine has also been prepared synthetically by the action of 



CAFFEINE GKOUP 287 

methyliodide on theophylline. It crystallizes in slender silky 
needles which melt at 234°. It is soluble in water 1 : 46, alco- 
hol 1 : 66, and in chloroform 1:8. Its solubility in water is 
increased by heat, citric acid, benzoates and salicylates, bromides, 
antipyrine and a number of other substances. Combinations, 
such as caffeine sodiosalicylate and caffeine sodiobenzoate, pre- 
pared by mixing caffeine with such solutions and evaporating the 
mixture, are used in medicine. The object is to increase solu- 
bility and to make the preparations available for hypodermic use. 

Theobromine is the chief alkaloid of cocoa beans and is found 
in small quantities in Kola nuts and leaves and in tea leaves. It 
has also been synthesized. Caffeine may be separated fairly 
well from theobromine by extraction with cold benzine in which 
theobromine is insoluble. 

Hypoxanthine, and guanine (6 oxy 2 amino purine) occur to- 
gether in a number of plants, especially, curcubita pepo, hordeum 
sativum. Hypoxanthine occurs free to some extent in animal 
tissues, especially muscles, more is found in the combined state. 

Xanthine is found in tea leaves, and the juice of beet root; 
theobromine, in theobroma cocoa; caffeine, in tea and coffee. 
Uric acid is not found in plants. The murexide test makes the 
recognition of the purine base an easy matter, but the identifi- 
cation of the individual members is a difficult task. Hypoxan- 
thine and xanthine when administered to man increase the uric 
acid to about 55 per cent, of the theoretical amount. 

Guanine is uually prepared from guano — hence the name. It 
occurs commonly in animal organisms and has been found in 
small quantities in yeast, sugar cane, and beet root. It has also 
been synthesized. Its main interest in pharmacology is its re- 
lation to the more important caffeine drugs. In the urine of 
pigs xanthine, hypoxanthine, with smaller amounts of adenine 
and guanine preponderate in amount over uric acid. The tissues 
of these animals are deficient in guanase, and the pig sometimes 
suffers from " guanine gout". Nitrous acid converts guanine 
into xanthine. This may also be accomplished by boiling it with 
hydrochloric acid. 

Adenine occurs in beet root, yeast, tea, and other plants and in 
the animal organism especially in the pancreas. Adenase converts 
it into hypoxanthine C 5 H 3 N 4 NH 2 + H 2 = C 5 H 5 N 5 + NH 3 . 



288 CHEMICAL PHARMACOLOGY 

Murexide Test 

Put 3 or 4 milligrams of caffeine in a white evaporating 
dish. Add a few cc. of saturated chlorine or bromine water and 
evaporate to dryness on a water bath. To the yellow residue 
add a drop of NH 4 OH. A bright purple color is produced. Nitric 
acid may be used to oxidize the caffeine instead of the chlorine 
water, but it is not so efficient. HC1 with a crystal of KC10 3 may 
also be used. This decomposes the purine bases to alloxan 
which, on reduction yields alloxantine: 

CO NH NH CO CO NH 

I I I I /OH HO.| | 

C = CO CO Of- ~C CO 

I I I I I I 

CO NH NH CO CO NH 

Alloxan Alloxantine. 

Alloxantine in presence of ammonia forms ammonium pur- 
purate or murexide. — NH4.C8H4N5O6 + H 2 

NH Q /x CO NH 

C = Cv-NH-/C CO 



NH C = CO NH 

Purpuric acid 

2. Caffeine is also precipitated by the alkaloid reagents. 
These tests are not characteristic. 

3. The melting point is 235-237°. It is soluble in 46 parts 
of water, 5.5 of chloroform, and in 530 parts of ether. 

Action of Caffeine Compounds 

Caffeine is used mainly as (1) a diuretic, and (2) as a stimulant 
to respiration and circulation, (3) for its influences on muscle, 
and (4) for its action on the nervous system. Theophylline has 
less action than caffeine on the central nervous system and heart 
but is a stronger diuretic, this diuretic action is said not to last 
as long as that produced by theobromine, which is a less powerful 
diuretic. Theobromine also acts less on the central nervous 



CAFFEINE 289 

system than caffeine. The other compounds have varying 
actions, but these are not important in medicine. 

1. The Diuretic Action of Caffeine. — Caffeine compounds are 
the diuretic drugs par excellence. Many laboratory exercises on 
this point fail because they do not consider the fundamentals of 
urine secretion or the condition in which caffeine acts best as a 
diuretic. First, the kidneys cannot secrete water unless water 
is present. While the blood normally contains over 90 per cent, 
water, this water is apparently in combination with colloid mate- 
rial and only free water can be secreted. In those clinical cases 
where caffeine compounds act to the best advantage, the tissues 
are water logged either because of inadequacy on the part of the 
heart, or change in the proteins, or salt retention. Caffeine 
under these conditions causes a diuresis either by causing a 
greater elimination of the free water or by liberating some of the 
combined water. In normal animals the change caused by 
caffeine on diuresis is so small that, as a class experiment, it is 
unsatisfactory. Only as much water as is taken in can be poured 
out, and in normal conditions this pouring out or urination pro- 
ceeds at a constant rate and is hastened but little by diuretics. 
To make a laboratory experiment show the real action of caffeine 
on the kidneys, the animal should be given a large volume of 
liquid a short time before the caffeine is administered. 

The action of caffeine is direct on the kidney because: 

1. There are no secreting nerves to the kidney. Diuresis 
occurs after section of all nerves and on the isolated kidney, and 
after degeneration of the nerves. 

2. The fluids in the tissues are not changed. 

3. The kidney increases in volume, when secreting: 

(a) The action therefore is local but may be either on the ves- 
sels—a circulatory action, or 

(6) It may be an action on the secreting cell. Opinion at 
present favors a direct action on the secreting cell : 

4. Rost 1 has found that the flow of urine is increased only 
when considerable caffeine passes into the urine. 

5. Richards and Plant 2 have shown that diuresis may occur with 
caffeine even when there is no change in kidney volume. 

1 Schniidebergs Archiv., 1895, vol. 36. 

2 Jour, of Pharmacology, 1915, p. 485. 

19 



290 CHEMICAL PHARMACOLOGY 

Fate of Caffeine in the Body 

In the body caffeine loses its methyl groups — first becoming 
dimethyl — then monomethyl xanthine. Then xanthine is formed 
and this may be broken down into urea. Of the monomethyl 
xanthines, 7 monomethyl is formed in greatest quantity. Of the 
dimethyl xanthines, paraxanthine — 1, 7 dimethyl xanthine is found. 
Both of these may be found in the urine after the ingestion of 
caffeine. While this is true for man there is some difference in 
the order in which the methyl groups are lost, in different 
animals. In the dog all three dimethylxanthines appear in the 
urine after larger doses of caffeine, although theophylline 1.3 
dimethylxanthine predominates; while in the rabbit under the 
same conditions and in man, paraxanthine or 1.7 dimethylxanthine 
predominates. The monomethyl xanthines are also excreted in 
different proportions in the various species of animal, but in man 
and the rabbit heteroxanthine — 7 methyl xanthine prevails. 

* Only about 10 per cent, of the ingested caffeine appears in 
the urine in the form of the above decomposition products. The 
rest is oxidized in the body to urea and other end products, car- 
bon dioxide and water. After the ingestion of 1 to 1.5 grams 
caffeine daily uric acid elimination is increased (Benedict). This 
is apparently due to a conversion of caffeine to uric acid, though 
it might also be due to a stimulation of the kidney to secrete the 
normal uric acid of the blood. 

The tolerance that is acquired from the prolonged uses of tea 
and coffee, is in great part due to the body acquiring the ability 
to oxidize these alkaloids more rapidly than at the beginning. 
This is not the only explanation, however, for large quantities 
may still be obtained from the tissues. 

Purin metabolism is especially interesting in relation to gout, 
in which an apparent deficiency of the oxidation of uric acid or 
an increased formation, or a change in combination exists. It 
has been found that when dogs, pigs or rabbits are fed nucleic 
acid, 90-95 per cent, of it can be recovered as allantoine, 3 to 6 
per cent, as uric acid and 1 to 2 per cent, as purin bases. It 
may be that in perverted metabolism more than the usual amount 
of purin bases is converted into uric acid. There is no increase 
in the uric acid content of the blood after the ingestion of foods 



CAFFEINE 291 

rich in purines except in cases of renal insufficiency, for this 
reason gout is looked upon as a beginning nephritis (Denis). 

In normal cases the oxidation of purin bases takes place as 
follows — hypoxanthine — » xanthine — * uric acid — > allantoine. It 
has been taught that allantoine was oxidized to CO2 and urea, 
but at present it is believed by many that allantoine is the end 
product of purine oxidation. The human organism cannot oxi- 
dize allantoine, since allantoine injected hypodermically in man 
has been completely recovered. 

It has been also found that 60 to 90 per cent, of uric acid ad- 
ministered hypodermically can be recovered in the urine. Some 
have found as much as 99 per cent, of that administered. Uric 
acid is oxidized with much greater difficulty in man than in 
monkeys, dogs, cats, rabbits or pigs. In fact no adequate evi- 
dence exists that the tissues of man can oxidize uric acid. Urea 
is formed from uric acid in vitro by a variety of oxidizing agents 
and allantoine is hydrolysed by boiling water into allanturic acid 
and urea, so that its resistance to oxidation in the body is difficult 
to understand. 

Economic Use of Caffeine 

Owing to the daily use of caffeine compounds in the form of 
tea and coffee, frequent cases of chronic poisoning are seen. 
The symptoms, mainly those of dyspepsia, are: epigastric 
uneasiness, depression, succeeded by nervousness, restlessness 
and excitement, tremors, disturbed sleep, anorexia, headache, 
vertigo, confusion, palpitation, constipation and hysterical dis- 
turbances. These symptoms are relieved by the gradual re- 
moval of the drug. No acute fatal case of caffeine poisoning is 
recorded and the fatal dose is not known, but it is over 10 grams. 
To avoid the symptoms of chronic poisoning and to allow the 
use of tea and coffee in 'susceptible individuals, numerous at- 
tempts to remove the caffeine from tea and coffee have been 
made. Some manufacturers have placed the blame for the 
nervous symptoms on the volatile oil content — the so-called 
caffeol — but this is insufficient to cause the symptoms, and the 
caffeine content is quite sufficient to explain all the untoward 
symptoms. 



292 CHEMICAL PHARMACOLOGY 

TO ILLUSTRATE IN GENERAL THE ISOLATION OF 

ALKALOIDS 

POWER AND CHESTNUT'S METHOD OF ASSAYING CAFFEINE IN 
VEGETABLE MATERIAL 1 

Ten grams of the finely ground material, previously moistened 
with a little alcohol, are extracted for about 8 hours in a Soxhlet 
apparatus with hot alcohol. The alcoholic extract is then added 
to a suspension of 10 grams of heavy magnesium oxide in 100 cc. of 
water, contained in a porcelain dish, the flask being rinsed with 
a little hot water, and this liquid added to the mixture. The 
mixture is allowed to evaporate slowly on a steam-bath or water- 
bath, with frequent stirring, until all the alcohol is removed and 
a nearly dry, powdery mass is obtained. This is mixed with 
sufficient hot water to enable it to be brought on a filter, which 
preferably should be smooth, and, after thoroughly cleaning the 
dish by means of a glass rod, to which a piece of rubber tubing 
is attached, the contents of the filter are washed with successive 
portions of hot water until about 250 cc. of filtrate is obtained. 
To the filtrate, contained in a flask of one-liter capacity, is added 
10 cc. of a 10 per cent, solution of sulfuric acid, which causes the 
liquid to become much lighter in color, and with some kinds of 
material, such as Ilex leaves, a considerable precipitate is pro- 
duced. In some cases, as with tea and guarana, it was found 
necessary to use 20 cc. of the above-mentioned acid in order to 
prevent the formation of an emulsion on subsequently extracting 
with chloroform. After the addition of the acid, a small funnel 
is placed in the neck of the flask, and the liquid, which is at first 
gently heated until any frothing ceases, is kept in a state of 
active ebullition for half an hour. This treatment is for the 
purpose of hydrolyzing any saponin that may be present. After 
being allowed to cool, the liquid is *passed through a double 
moistened filter into a separatory funnel, the flask and filter 
being washed with small portions of about 0.5 per cent, sulfuric 
acid. The clear acid filtrate is then shaken with 6 successive 
portions of chloroform of 25 cc. each, which usually separates 
sharply and quickly, but, if not, can be made to do so by gently 

1 The Journal of the American Chemical Society, Vol. xli, No. 8, August, 
1919. 



CAFFEINE 293 

rotating the separately funnel, or, if necessary, by the use of 
somewhat larger portions of chloroform. The united chloroform 
extracts are brought into another dry separ'atory funnel and 
shaken with '5 cc. of a 1 per cent, solution of potassium hydroxide, 
which serves to remove coloring matter. After complete sub- 
sidence of the chloroform solution it is passed through a small, 
dry filter into an Erlenmeyer flask, the alkaline liquid remaining 
in the separatory funnel being subsequently washed with two 
successive portions of chloroform of 10 cc. each. These washings 
of the alkali are passed through the previously mentioned filter, 
and, after washing the latter with a little chloroform, they are 
added to the first chloroform solution. The chloroform is finally 
removed by distillation from a water-bath the residual caffeine 
brought by means of a little chloroform into a tared beaker, and, 
after the solvent has been allowed to evaporate spontaneously, 
the caffeine is dried for half an hour in a water-oven and weighed. 
On heating for another half an hour there is usually a further 
slight diminution of weight, and this second weighing may be 
considered to represent the correct amount of caffeine, which, 
when multiplied by ten, denotes the percentage. As so obtained 
the caffeine is nearly colorless, and possesses a quite satisfactory 
degree of purity. 

ISOLATION OF CAFFEINE 

The most important source of caffeine is tea and coffee. To 
separate and estimate the amount of caffeine in tea and coffee : 

Keller's Method. — Take 6 grams of tea leaves and place them 
in a separatory funnel. Add 120 grams of chloroform. Shake 
and in a few minutes add 6 cc. 10 per cent, solution of NH 3 . 
Shake repeatedly during a period of 30 minutes. Let stand for 
3 to 6 hours or until the solution is clear and the leaves have 
absorbed all of the water. Filter through a paper moistened 
with CHC1 3 and collect 100 grams in a small weighed flask. 
This represents 5 grams of the tea. Evaporate the chloroform 
over a water bath. Pour 3-^ cc. of absolute alcohol on the resi- 
due and heat on the water bath to drive off the alcohol. The 
residue represents chlorophyll, fat, caffeine, etc., or CHC1 3 ex- 
tract. To purify this add 10 cc. 30 per cent, alcohol, heat on 
a water bath. The caffeine passes into solution. The coloring 



294 CHEMICAL PHARMACOLOGY 

matter forms in lumps and can be filtered off. Pass the solution 
through a filter and wash the filter with 10 cc. of water. Evapor- 
ate the filtrate on a small weighed evaporating dish to dryness 
on a water bath. The residue is nearly pure caffeine. Calculate 
the per cent, in the original tea. The tea is thus assayed. 

High heat decomposes organic substances, hence a water bath 
is used in this assay. The ammonia liberates the free alkaloid 
which is readily soluble in the chloroform. The ammonia also 
combines with tannic acid, the amount of which depends on the 
variety of the tea. 

This method may also be used for coffee and cola preparations. 
There are other much more refined and elaborate methods for 
estimating caffeine, than this one. 

UNCLASSIFIED ALKALOIDS 

Veratrine is a mixture of alkaloids of unknown composition. 
The effects of veratrine resemble closely those of aconite (qv). 
In addition the muscles are stimulated and relaxation greatly 
prolonged. The chief tests are : 

1. Concentrated sulphuric acid added to veratrine gives an 
intense yellow color, which changes to orange and finally cherry 
red. 

2. Concentrated hydrochloric acid gives a cherry red color 
only after heating 10-15 minutes on a water bath. 

3. Vitali's test: Dissolve veratrine in a few drops of fuming 
nitric acid and evaporate to dryness on a water bath, a yellow 
residue remains which when moistened with alcoholic potash gives 
an orange red or red violet color. 

Atropine, hyoscyamine, scopolamine and strychnine also give 
this test. 

4. Physiological test : When 0.5 cc. of 0.1 per cent, veratrine 
is injected into the lymph sac of a frog, a muscle preparation 
prepared after 30 minutes shows an enormously increased relaxa- 
tion period. 

Physostigmine or Eserine. — C15H21Q2N3 is an alkaloid found 
in calabar bean. Its composition is unknown. It has a con- 
siderable use in medicine and resembles muscarine and pilocarpine 
in action but has a greater effect on parenchymal tissue. Its 
chief actions arc: 



COLCHICINE 295 

1. Marked constriction of the pupil and spasm of the ciliary 
muscle, seen as a rule only when applied locally. 

2. A powerful stimulation of the muscular mechanism of all 
muscles innervated by the parasympathetic system especially 
the gastro-intestinal system. 

3. A stimulation of the vagus endings to the heart. 

4. Some initial stimulation followed by depression, of the 
medullary centers and spinal cord. 

TESTS 

1. Light and heat cause solutions to turn red on standing. 

2. If a physostigmine salt is evaporated to dryness and am- 
monium Irydroxide added a bluish green residue remains. 

3. Nitric acid dissolves physostigmine forming a yellow 
solution. 

4. If a solution of physostigmine is shaken with an excess of 
NaOH solution, a red coloring matter rubroserine is formed. 
Crystals separate on standing which become greenish blue. 

5. A solution of eserine dropped in the eye of a rabbit or cat 
causes constriction of the pupil. Atropine will remove the 
constriction. 

Colchicine. — This is an alkaloid of unknown composition. It is 
found in all parts of meadow saffron, and is used in the treatment 
of gout. When hydrolysed with H 2 S0 4 it yields colchicein and 
methyl alcohol 

C 22 H 25 N0 6 + H 2 = C 21 H 23 N0 6 + CH 3 OH 
colchicine Colchiceine 

In toxic doses it causes acute intestinal pain with nausea 
vomiting and diarrhoea. The lethal dose is about .0012 gram 
per kilo of body weight. Death is due to vasomotor paralysis. 

Tests 

Unless the aqueous solutions have a yellow color colchicine is 
absent. It may be confused with dilute sols, of picric acid. 

1. Precipitation occurs by the general alkaloidal reagents. 

2. Concentrated nitric acid dissolves colchicine with a dirty 
yellow color changing to red and finally yellow. Addition of 
NaOH produces an orange red or orange yellow color. 



296 CHEMICAL PHARMACOLOGY 

3. Concentrated sulphuric acid dissolves colchicine with an 
intense yellow color. A drop of concentrated nitric added to 
this produces a green, blue, violet and finally yellow color, an 
excess of KOH will now produce a red color. 

Unclassified or Alkaloids of Unknown Composition. — The 
most important are the aconite alkaloids: 

Aconitine : Acetylbenzoylaconine 

C 21 H 27 3 N(OAc) (OBz) (OCH 3 ) 4 
Bikhaconitine : Acetylveratroylbikhaconine 

C 21 H 27 ON(OAc)(OVe)(OCH 3 ) 4 
Indaconitine : Acetylbenzoylpseudaconine 

C 21 H 27 2 N(OAc) (OBz) (OCH 3 ) 4 
Japaconitine : Acetylbenzoyljapaconine 

C 21 H 29 3 N(OAc) (OBz) (OCH 3 ) 4 
Pseudaconitine : Acetylveratroylpseudaconine 

C 21 H 27 2 N(OAc) (OVe) (OCH 3 ) 4 
Ac = acetyl; Bz = benzoyl; Ve = veratroyl. 

The Quebracho Alkaloids. 

Aspidosamine, C 22 H 28 2 N 2 . 

Aspidospermatine, C 22 H 28 2 N 2 . 

Aspidospermine, C 22 H 30 ON 2 . 

Hypoquebrachine, C 2 iH 26 2 N 2 . 

Quebrachamine 

Quebrachine, C 2 iH 26 3 N 2 . 

Ergotoxine. 

Ergotoxine, C35H41O2N5 . 

Ergotinine, . C 3 5H 39 5 N5. 

The Colchicine Alkaloids. 

Colchicine, C 22 H 25 2 N , 

Colchicine, C 21 H 23 6 N.KH 2 0. 

Yohimbinine, C 35 H 45 6 N3 

Yohimbine, C 22 H 3 oOeN 2 

Cytisine, C n Hi 4 ON 2 . 

The amount of any, known alkaloid can be determined by 
dissolving it in an excess of normal acid and titrating the excess 



ALKALOIDS 297 

of the acid, just as ammonia is titrated. We know that 1 cc. of 
each normal solutionis equivalent to 1 cc. of every other normal 
solution. If we titrate NH 4 OH with H 2 S0 4 the reaction is as 
follows : 

H 2 S0 4 + 2NH 4 OH = (NH 4 )oS0 4 + 2H 2 
lcc. of normal H 2 S0 4 = therefore . 014 grams N or 
1 cc. of N/10 H 2 S0 4 = . 0014 grams N or 

.0017 grams NH 3 

The factors for the various alkaloids differ depending on the 
molecular weight of the alkaloid, but 1 cc. n/10 H 2 S0 4 always 
represents .0014 N in the alkaloid just as it does in ammonia, but 
while the molecular weight of NH 3 is 17, that of atropine is 289.19. 
Hence, the amount of atropine equivalent to 1 cc. n/10 H 2 S0 4 
is 17 : 289.19 :: .0017 :X = .029-. 

The amount of each alkaloid represented by 1 cc. n/10 H 2 S0 4 
is as follows : 

Aconitine . 0645 

Atropine 0.0289 

Brucine 0.0394 

Cocaine 0.0303 

Coniine 0.0127 

Morphine + H 2 0.0303 

Physostigmine 0.0273 

Pilocarpine 0.0208 

Quinine 0.0324 

Strychnine 0.0334 

Combined alkaloids of Cinchona . 0309 

Combined alkaloids of Ipecac . 0240 

THE PHYSIOLOGICAL SIGNIFICANCE OF NITROGEN 

BASES 

Since many of these bases are exceedingly reactive in animals 
one wonders what role they play in the life of the plant. Three 
views are held regarding this: 

1. They are the end product of plant metabolism rendered 
harmless to the plant and correspond to the urea and uric acid, 
of animals. This view is generally accepted. 



298 CHEMICAL PHARMACOLOGY 

2. They are protective materials, against the attack by ani- 
mals and parasitic fungi. 

3. They are nutritive or plastic material used by the plant 
in metabolism. 

In favor of the first view is the fact that the purine bases 
generally are formed in places of great cellular activity, and 
their disappearance is never accompanied by a simultaneous 
increase in albuminous substances. Again Kerbosch has pre- 
sented evidence to show that narcotine is formed from protein 
during the germination of poppy seeds. Caffeine and theobro- 
mine are generally held to be decompositive products of protein. 
The difference in plants and animals in this regard is that animals 
have a mechanism for the elimination of these waste products 
while in plants there is no such elimination. 

The view that they are protective against animals and fungi 
has little to recommend it since plants grow just as well in lati- 
tudes where no alkaloid or much less is formed. 

There is little evidence to show that they are nutritive since it 
has been shown that in the germination and early growth of 
potatoes, nux vomica, thorn apple, and other seeds there is no 
change in the alkaloid content. Certain lower forms of plant 
life, that do not contain alkaloids, can utilize atropine, cocaine, 
morphine in their growth. Strychnine is toxic to some, quinine 
to others. 

XXVII. PROTEINS 

The name protein comes from the Greek word Protos, first, 
and in the animal body they are of the first importance. In 
plants, carbohydrates constitute the greater part, with some pro- 
tein, while in the animal, the greater part of the living matter is 
made up of protein with some carbohydrate always associated. 

Proteins, fats and carbohydrates, are organic materials, and 
are always associated with life. Some authors hold that the pro- 
tein molecule in life is in a labile form, probably due to the pres- 
ence of aldehyde and nitril groups. When life ceases, there is 
an intramolecular rearrangement, to the stable or dead form. 
The vibration or movement of the protein molecule is life. 
Whether this movement ever can be analysed or imitated the 



PROTEINS 299 

future only can tell. Progress in pharmacology, however, must 
consist to a great degree in a study of chemical protein reactions. 

CLASSIFICATION OF PROTEINS 

Owing to the complexity of the proteins, and to the fact that 
their chemistry is still to a great extent unknown, and still the 
subject of research, the nomenclature is continually changing. 
The American Society of Biochemists and the American Physio- 
logical Society, have agreed on the following classification : 
I. Simple proteins. 

II. Conjugated or compound proteins. 
III. Derived proteins. 

THE SIMPLE PROTEINS 

These on hydrolysis yield only monoamino acids. They are 
subdivided into: 

A. Albumins. — These are soluble in water and dilute saline 
solutions. They are coagulable by heat in neutral or acid solu- 
tion. They are not precipitated by saturation with NaCl, or 
MgS0 4 . Unless the reaction be acid they are precipitated by 
saturation with ammonium sulphate. They are rich in sulphur 
and yield no glycocoll on hydrolysis. 

The typical albumins are egg white, serum albumin, ]act 
albumin, legumelin of the pea and leucosin of the wheat and 
other cereals. Traces of albumin are found in all seeds. 

B. Globulins. — These are insoluble in water but soluble in 
dilute saline. In neutral solution they are precipitated by sat- 
uration with magnesium sulphate or hah saturation with am- 
monium sulphate. They can be separated from the albumins 
by dialysis. They are found associated with albumins. The 
albumins and globulins are the only proteins that are coagulated 
by heat; but many vegetable globulins differ from those of animal 
origin in that they are coagulated by heat with difficulty. Serum 
globulin and edestin are the chief representatives. They are 
the commonest form of the reserve protein of plants. 

C. Glutelins. — These are insoluble in water and neutral saline, 
but dissolve in dilute acid or alkali. Only two are known, 
glutenin found in wheat and oryzenin in rice. They are hard to 
prepare pure and have been but little investigated. 



300 CHEMICAL PHARMACOLOGY 

D. Prolamines or Gliadins. — These are vegetable proteins 
found in cereal grains only. They are insoluble in water or 
saline, soluble in 70-90 per cent, alcohol, soluble in dilute acids 
or alkalies. On hydrolysis they yield a considerable amount 
of proline — hence the name prolamine. Gliadin, hordein, zein 
are the chief representatives. 

E. Albuminoids. — These are insoluble in water, or in dilute 
acid, alkali, or saline. Elastin, keratin, and collagen are the 
chief members. They are found on connective tissue, skeletal 

-tissue, hair epidermis especially. On hydrolysis these are lacking 
in certain amino acids such as cystein, tyrosin and tryptophane. 

F. Histones. — These are strongly basic, soluble in water and 
dilute acid, and insoluble in ammonia. They are characterized 
by being precipitated by ammonia. They are related to the 
protamines, but are more complex than these. They have been 
prepared mainly from bird's blood corpuscles and the thymus 
gland. 

G. Protamines. — These are strongly basic. They are the 
simplest proteins known, and usually associated with nucleic 
acid. They are soluble in ammonia and yield large amounts of 
diamino acids sturin, salmin, clupein, etc., on hydrolysis. 

No compounds of this kind have been isolated from plants. 

CONJUGATED PROTEINS 

These are combinations of simple proteins with a non-protein 
group, which is usually acid in character. This group is some- 
times called the prosthetic group (prosthesos — additional). The 
group is subdivided as follows : 

A. Hemoglobins or Chromoproteins. — In these the* prosthetic 
group is colored. The representatives are hemoglobin, hemocy- 
anin, phycoerythrin, and phyocyan. 

B. Glyco or glucoproteins, represented by mucin, ichthulin, 
mucoids. The prosthetic group is a carbohydrate. 

C. Phosphoproteins. — Compounds of a simple protein with an 
unidentified phosphorus containing prosthetic group — casein and 
vitellin are types. 

D. Nucleoproteins. — These are perhaps the most important 
conjugated protein. They are combinations of protein with 



PROTEINS 301 

nucleic acid, and are found in the nucleus and chromatin. 
Nuclein and nucleolustone. 

E. Lecitho proteins, the prosthetic group is lecithin or a phos- 
pholipid English chemists do not recognize this group. They 
probably exist, though none has been isolated. 

F. Lipoproteins. — The existence of this group is also doubtful. 
They are supposed to be combinations of proteins and a higher 
fatty acid. 

DERIVED PROTEINS 

This group includes products formed from the simple proteins 
by hydrolysis. 

A. Primary Products 

(a) Proteans. — These are the incipient or first products formed 
on digestion. Edestan, myosan. 

(6) M eta-proteins. — These are products of the further action 
of acids and alkalies on proteins. They are soluble in weak acids 
and alkalies but precipitated on neutralization. Acid and 
alkali albumins are examples. 

(c) Coagulated Proteins. — These are insoluble proteins formed 
by the action of heat, alcohol, etc. 

B. Secondary or Intermediate Protein Derivatives 

(a) Proteoses. — These are hydrolytic cleavage products of 
proteins that are soluble in water, and not coagulated on heating. 
They are completely precipitated by saturation with ammonium 
sulphate. 

(b) Peptones. — These hydrolytic products are not precipitated 
by ammonium sulphate. They give the biuret reaction and are 
diffusible. 

(c) Peptides or Polypeptides. — These are compounds of 
amino acids of known composition, such as leucyl glutamic acid. 
Many are synthetic. They are called di, tri, tetra — etc. accord- 
ing to the number of amino acids in the molecule. They are not 
coagulable by heat, are diffusible, and may or may not give the 
biuret reaction. 



302 CHEMICAL PHARMACOLOGY 

The English Biochemists classify proteins as follows: 

I. Simple Proteins 

1. Protamines 

2. Histones 

3. Globulins 

4. Albumins 

5. Glutelins 

6. Gliadins. (Prolamins) (Soluble 70-90 per cent, alco- 
hol; insoluble in water). 

7. Sclero-proteins. (Forming the skeletal structure of 
animals) . 

8. Phosphoproteins. Caseinogen. 

II. Conjugated Proteins 

1. Chromoproteins 

2. Nucleoproteins 

3. Gluooproteins. 

III. Hydrolyzed Proteins 

1. Metaproteins 

2. Albumoses or proteoses 

3. Peptones 

4. Polypeptides 

COMPARISON OF ANIMAL AND VEGETABLE PROTEINS 

The general properties of these are the same, but there are 
some striking individual differences: With the exception of 
diamino trihydroxy-dodecanic acid, a hydrolytic product of 
casein, all the products of hydrolysis of animal protein have been 
found in plant protein. 

Vegetable proteins as a rule yield more glutaminic acid, 
proline, arginine, and ammonia than animal proteins. 

Prolamins or alcohol soluble proteins are found only in plants. 
None have so far been found in animals. 

AMINO ACIDS FOUND IN PLANTS 

Leucine has been found in the sprouts and buds of the horse 
chestnut. 

Iso-leucine in the residue of molasses. 



GENEEAL PROPERTIES OF PROTEINS 303 

Arginine in etiolated pumpkin seeds, in conifer seed, and in 
lupin seed. 

Phenyl-alanin in germinating lupin seeds. 

Tyrosine has been isolated from a number of growing shoots. 

Tryptophane in the seedlings of several species of legumes. 

Proline is obtained on the hydrolysis of a number of vegetable 
proteins, but has not been found free in any plant. 

GENERAL PROPERTIES OF PROTEINS 

The following are some of the more prominent properties of 
the group : 

I. Proteins are colloids (some have been prepared in crystalline 
form). They will not diffuse through a membrane. 

II. The ultimate elements are present in a certain proportion 
varying only within narrow limits. 

C 50.6-54.5 percent. 

H 6.5- 7.3 per cent. 

N. .: 15.0-17.6 percent. 

S 0.3-2.2 percent. 

P 0.4- 0.85 per cent. 

O. 21.4-23.5 percent. 

III. Proteins give precipitation and color reactions. The 
color depends upon certain chemical groups or complexes within 
the protein molecule, while the precipitate is due to a new com- 
pound formed with the reagent. Heavy metals and the alka- 
loidal reagents precipitate the proteins. 

Color Reactions 

1. Millon's reaction depends upon the presence of a mono- 
hydroxy benzene nucleus group. 

2. The xantho-proteic (xanthos-yellow) reaction is given by 
all proteins containing the benzene nuclei in the molecule. 

3. Adamkiewicz's reaction is given only by bodies which con- 
tain the indol groups. 

4. The biuret reaction has some relation to the amine group 
linked to carbon. 

CONH 2 CSNH 2 C(NH)NH 2 CH 2 NH 2 etc. 



304 



CHEMICAL PHARMACOLOGY 



Precipitation Reactions 

The following reagents cause precipitation of most proteins. 
Exceptions may be seen under the classification of proteins : 

1. Alcohol. 

2. Boiling or heat. 

3. Mineral acids. 

4. Solutions of salts of heavy metals. 

5. Excess of the salts of the alkalies. 

6. Potassium ferro-cyanide in acid reaction with acetic acid. 

7. Tannic acid in acid reaction with acetic acid. 

8. A solution of phosphotungstic or phosphomolybdic acid, 
after acidification with a mineral acid. 

9. Iodine in potassium iodide (Lugol's solution). 

10. Picric acid. 

11. Precipitins. 

Hydrolytic Products 

(IV) When hydrolysed proteins split into definite complexes, 
albuminoses, peptones, polypeptids, amino acids, etc., which are 
constant for the same, but vary for each protein. 

Twenty-one amino acids have been prepared from protein. 
They are as follows: 

A-Mono-amino — mono-carboxylic fatty acids: 

H H H 



H— C— NH 2 

1 


H 


-C— H 

1 


H— C-^-H 

1 


1 
0=C— OH 


H- 


1 
-C— NH 2 

1 


1 
H— C— H 

1 


k 


0: 


1 
=C— OH 


1 
H— C— NH 2 


C 2 H 5 N0 2 




C,H 7 N0 2 


0=C— OH 
C4H9NO2 


Glycocoll 




Alanine 


(a-amino 


(a-amino acetic 




(a-amino 


butyric 


acid) 




propionic 
acid) 


acid) 



H 

H— C— H 

I 
H— C— H 

H— C— H 

H— C— NH 2 

I 
0=C— OH 

C 6 HiiN0 2 

(a-amino 

valerianic 

acid) 



AMINO ACIDS 

CH 3 



305 



CH 3 
C— H 

H— C^-NH. 

I 
0=C— OH 



C5H11NO2 

Valine 

Iso-propyl 

acetic acid) 



H 
H— C— H 
H— C— H 
H— C— H 
H— C— H 

H— C— NH 2 

I 
0=C— OH 

CeHuNOs 

(a-amino normal 
caproic acid) 



CH3 CH3 

\/ 
C— H 

I 
H— C— H 

H— C— NH 2 

0=C— OH 



CH 3 

H— C— H CH 3 

\/ 
C— H 

H— C— NH 2 

0=C— OH 



C 6 H 13 N0 2 

Leucine 

(a-iso 

butyl 

a-amino 

acetic 

acid) 



C 6 H 13 N0 2 

Iso-leucine 
(ethyl, methyl 
a-amino propionic 
acid) 



20 



306 



H 

H— C— OH 

\ 
H— C— NH 2 

0=C— OH 

C3H7NO3 
Serine 
(B-hydroxy 
a-amino 
propionic 
acid) 



CHEMICAL PHARMACOLOGY 

H 



H— C— SH 

I 
H— C— NH 2 

0=C— OH 
C 3 H 7 NS0 2 

Cysteine 
(B-thio, a-amino 
propionic acid) 



H 



H 



H— C— S — S— C— H 

NH 2 — C— H H— C— NH 2 

I I 

0=C— OH 0=C— OH 

C6H12N2S2O4 
(Cystine) 

B. Mono-amino dicarboxylic acids 

0=C— OH O^C— OH 



H— C— H 
H— C— NH 2 
0=C— OH 



C 4 H 7 N0 2 
Aspartic acid 
(a-amino 
succinic acid) 



H— C— H 

I 
H— C— H 

H— C— NH 2 

I 
0=C— OH 

C5H9NO2 
Glutamic acid 
(a-amino glutaric 
acid) 



AMINO ACIDS 

C. Isocyclic amino acids 
C— OH 
HC CH 



307 



HC CH 

V 

c 

H— C— H 

I 
H— C— NH 2 

I 
= C— OH 

C 9 HnN0 3 

Tyrosine 
(/3-para-hydroxy- 
phenyl, a-amino 
propionic acid) 



CH 

•\ 

HC CH 



HC CH 

\/ 
C 

! 

H— C— H 

I 
H— C— NH 2 

I 
= C— OH 
C^HnNOa 

Penyl alanine (/3-phenyl 
a-amino-, propionic acid) 



D. Heterocylic amino acids 

H NH 2 

I I II 
-C— C— C— C— OH 

I II II II I 

HC C C H H 



CH 
HC C- 



CH NH H 

C11H12N2O2 (Tryptophane) 
(a-amino, /3-indole 
propionic acid) 



H 2 C CH 2 O 



H 2 C C— C— OH 



NH H 

C5H9NO2 (Proline) 
(a-pyrrolidine carbox- 
ylic acid) 



308 



HC— N 

\ 

C— NH 



CHEMICAL PHARMACOLOGY 
H 2 C 



CH 



HC— H 

H— C— NH 2 

I 
0=C— OH 

C 6 H 9 N 3 2 
Histidine 
(a-amino, ^-imidazole 
propionic acid) 



CHOH 
O 



H 2 C C— C— OH 

\/\ 
NH H 



C 5 H 9 N0 3 

Oxy-proline 
(The position of the hydroxyl 
is uncertain) 



E. Mono-carboxylic, diamino acids 

NH 2 

I 
C=NH 

N— H 

H— C— H 

H— C— H 

! 

H— C— H 

I 
H— C— NH 2 

0=C— OH 

C 6 H 14 N 4 2 
Arginine 
(a-amino, d-guanidine 
valerianic acid) 



NH 2 

H— C— H 

I 
H— C— H 

I 
H— C— H 

I 
H— C— H 

H— C— NH : 

! 

0=C— OH 



C 6 H 14 N 2 2 
Lysine 
(a, e, amino, caproic 
acid) 



GENERAL CHARACTERS OF AMINO ACIDS 

I. Reaction. — The mono-carboxylic mono-amino acids are 
amphoteric to litmus. The diamino acids, and arginine and 



AMINO ACIDS 309 

histidine are alkaline, and in solution absorb C0 2 . The mono- 
ainino dicarboxylic acids are acid to litmus. 

II. Solubility. — As a rule they are soluble in water. Tyrosine 
is but slightly soluble in cold but is soluble in hot water. They are 
soluble in dilute acids and alkalies. They are insoluble in ether. 

III. Combinations. — Since amino-acids contain both NH 2 
and COOH group they will unite with both acids and bases. The 
NH 2 group unites with acids as does ammonia. The COOH 
group unites with NaOH etc. to form salts of the amino acid. 
Through the amino group they unite with salts of the heavy 
metals, such as Cu, Pt, Ag, Hg etc. to form such combinations as 
- CH 3 .CH 2 .CH.NH 2 CuCl 2 .COOH. These salts are insoluble in 
water. 

IV. Condensation. — Amino acids may condense or unite with 
each other to form polypeptides. The amino group of one uniting 
with the carboxyl group of another. Such combinations are two 
molecules of glycocoll or glycyl-glycine : 

NH 2 CH 2 CO.NHCH 2 COOH and 
Leucyl — asparagine : 

COOH 

CH 3x 

)CH.CH 2 .CH(NH 2 )CO.NH.CH 
CH 3 X | 

CH 2 

CONH 2 

A great number of such polypeptides have been prepared and 
are named di, tri, penta, etc. according to the number of amino 
acids in the combination. The most complex of these so far 
synthesized contained 18 amino acids, and contained three 
leucine and 15 glycocoll groups. It was 1-leucyl-triglycyl-l- 
leucyl - triglycyl - 1 - leucyloctoglycylglycine. NH 2 CH (C 4 H 9 ) CO. 
(NHCH 2 CO) 3 .NHCH(C 4 H9)CO.(NHCH 2 C03).NHCH(C4H9) 
CO. (NHCH 2 CO) 8 NHCH 2 COOH . 

CONDENSATION PRODUCTS 

The alpha amino acids readily condense by the elimination of 
water from the COOH groups : 



310 CHEMICAL PHARMACOLOGY 



CH 2 NH| H HO] PC CH 2 NH OC 

I I | | + 2H 2 

C O'OH H[ HN CH 2 -> CO— HN — CH 2 

Beta amino acids condense through loss of ammonia with the 
formation of unsaturated acids : 



|NH 2 | CH 2 CH |HlCOOH = NH 3 + CH 2 : CH.COOH 

B. amino propionic acid acrylic acid 

Amino acids through the loss of water yield inner anhydrides 
which, because of the similarity to lactones, are called lactams: 

CH 2 CH 2 CH 2 CO CH 2 CH 2 CH 2 CO 



NH(H OH) HN 

Amino butyric acid — » lactam of aminobutyric acid 

Lactones are the inner anhydrides of gamma and delta hy- 
droxy acids, i.e., instead of the amino group in amino acids a 
hydroxyl group may be substituted. Such condensations as 
these may explain the formation of alkaloids in plants. Thus 
when solutions of leucine are evaporated diketo condensation 
imides are formed : 

O 

II 
(CH 3 ) 2 =CH— CH 2 — CH.NH— C 

I 
0=C— NH— CH— CH 2 — CH=(CH 3 ) 2 . 

Leucinimide (Diisobutyl-diketopiperazine) 

This gives rise to diketo piperazine from which piperazine may 
be prepared: 

NH CH 2 — CH 2 

/ \ 

HN NH 

\ / 

CH 2 — CH 2 

piperazine 



H 2 C CO 

I I 
CO CH 2 



NH 
Diketo piperazine 



LACTIM UKIC ACID 



311 



From the pharmacological point of view, lactams are interesting 
preparations producing strychnine like convulsions in animals. 
This is a common characteristic of ring compounds. The amino 
acids themselves are devoid of visible action. Such molecular 
rearrangements may be the cause of many obscure reactions in 
indigestion, uremias, gout, etc. 

The precipitation of urates in gout according to some (Gudzent) 
is due to uric acid changing from the lactam to the lactim form. 
The lactim form of uric acid is : 



N = C— OH 

| ! 

HOC C— NH 



\ 



COH 



• 



N C- 



-N 



Cf. formula p. 284. 

Piperazine has been advocated in the treatment of gout, but 
it is without influence. 

Condensation with Formaldehyde 

Ammonia condenses with formaldehyde to form hexamethylene 
tetramine. The product formed in this case is N 4 (CH 2 )6. 

The amino acids also condense with formaldehyde according 
to the formula. 



NH 2 
O 



N = CH, 

I O 



R— C— C— OH+HC = = R— C— C— OH+H 2 



H H H 

Methylene amino acid 

This methylene derivative has no basic properties and can be 
sharply titrated with alkali. This is the basis for the Sorensen 
titration method for the titration of amino acids in a mixture. 
This is perhaps one of the mechanisms in the formation of 
amino acids in plants and animals. Erlenmeyer and Kunlin 1 

x Ber. deut. chem. Gesells. 1902-35-2438. 



312 CHEMICAL PHARMACOLOGY 

were able to synthesize formyl derivatives of alanine and glycine 
by the interaction of ammonia and glyoxylic acid, and since both 
of these occur in plants, the probability of such formation in the 
plant is suggested. 

CHO CH 2 NH CHO 

2 I +NH 3 = I 

COOH COOH+H 2 0+C0 2 

Glyoxylic acid Formyl-glycine 

CH 2 NH CHO CH 2 NH 2 

+ H 2 -* -f-HCOOH 

COOH COOH 

Formyl-glycine Glycine 

THE DEAMINIZATION OF AMINO ACIDS 

In the preparation of amino acids from protein, the usual 
method is to boil the protein with acid for hours. This fact 
shows the stability of the amino groups in acid solution. The 
slight amount of nitrogen that is evolved is in the amide condi- 
tion, that is, in the form of R.CONH 2 . Amino acids are also 
quite stable in alkaline solution. Arginine decomposes to orni- 
thin and urea, and cystine and cysteine lose considerable of their 
sulphur, but as a rule little decomposition occurs. 

Oxidation may cause deaminization through splitting off 
ammonia. Various oxidizing agents like hydrogen peroxide, 
and potassium permanganate, cause, in vitro, the deaminization 
as follows: 

CH3 CH3 

! I 

H— C— NH 2 + O ±=> C=0 + NH 3 

I I 

0=C— OH 0=C— OH 

Alanine Pyruvic acid 

Where deaminization takes place in the body is not known. 
It seems that all tissues, perhaps due to a ferment, have deaminiz- 
ing properties. It is thought by some that since no amino acids, 
or only a trace, can be demonstrated in the blood, that deaminiza- 
tion takes place in the intestine. There is no direct proof that 



CARBAMINO REACTION 313 

the intestine possesses this property to a greater extent than any 
other tissue. 

URETHANE FORMATION OR THE CARBAMINO REACTION OF 

AMINO ACIDS 

Chloroformic ester reacts with ammonia to form urethane or 
amino ethyl-formate — or the ethyl ester of carbamic acid. 

/CI /NH 2 

CO( + NH 8 = CO<^ + HC1 

X OC 2 H 5 X OC 2 H 5 

Ammonium carbamate is formed as follows: 

O O 

II II 

HO— C— OH + 2NH 3 ^NH 4 — C— O— NH 2 

+ H 2 
Carbonic acid 

Urethane is the ethyl ester of ammonium carbamate, and a 
reaction of this kind is known as the carbamino reaction. 

Ammonium carbamate is the intermediary compound in the 
formation of urea in the body. 

/NH 2 
NH 2 - COONH4 = CO^ + H 2 

X NH 2 
Ammonium carbamate, urea or carbamide. 

Carbamate salts, differ from carbonates in their solubilities, 
X>Ca 
2CO(^ or calcium carbamate being soluble in water. 

X NH 2 
When boiled however calcium carbonate is formed and NH 3 is 
driven off. This difference in the solubilities is used to advantage 
in determining the composition of mixtures of amino acids. If in 
a solution containing amino acids the C0 2 formed is equivalent 

CO 

to the N, or -^- = 1 the relation is that of mono-amino acids. 

If diamino acids or polypeptids are present the ratio is less than 1. 



314 CHEMICAL PHARMACOLOGY 

The Taste of Amino Acids 

There is nothing distinctive in the taste of amino acids. Gly co- 
coll as the name indicates is sweet. Alanine and glycoleucine 
are also sweet. Leucine is tasteless and iso-leucine is bitter. 
Taste in relation to chemical structure is not well understood. 
See p. 205. 

OPTICAL PROPERTIES OF AMINO ACIDS 

The alpha atom of amino acids is asymmetric, consequently 
the acids are optically active. The presence of the asymmetric 
C atom does not necessarily confer optical activity, but no opti- 
cally active organic substance is known without the asymmetric C 
atom. Like most natural products many amino acids are levoro- 
tatory; proteins also are levorotatory and on hydrolysis the 
rotation increases, so that the rate of digestion can be measured 
by increase of optical activity. 

Knowing the formula of a compound it is impossible to tell 
what direction the rotation may be, and when one group is sub- 
stituted for another prediction of the change can not be made. 

It is possible by substituting one group for another to transform 
an optically active compound into its optical antipode. This is 
known as Walden's inversion. In several cases it has been 
possible to start with a substance and by a reaction cycle obtain 
the optical antipode and again the original substance Walden 
treated 1. Chlorsuccinic acid with moist silver oxide and obtained 
1. malic acid. This on treatment with phosphorus pentachloride 
was converted into d. chlorsuccinic acid, which was converted 
into d. malic acid which on treatment with phosphorus pentach- 
loride yielded 1. chlorsuccinic acid. 

These transformations are diagrammed in the following scheme : 

AgOH 

1-Chlorosuccinic acid > 1-Malic acid 

|PC1 5 | PC1 5 

AgOH 

I 
d-Malic acid<— d-Chlorosuccinic acid 

With alanine, and nitrosyl bromide — Emil Fisher worked out 
the following reaction cycle: 



OPTICAL PROPERTIES 



315 



NOBr 



d-Alanine- 



NH S 



d-Bromopropionic acid- 



-Bromopropionic acid 



-1-Alanine 



The significance of optical activity in so far as amino acids 
are concerned, and in general, is little understood. A knowledge 
of the cause of these facts would do much to advance the under- 
standing of drug action. 

The facts that certain moulds can ferment dextrotartaric 
acid and not levo; that yeast will ferment such sugars as d- 
mannose d-glucose, or d-fructose, but will not ferment 1-fruc- 
tose, 1-glucose, 1-mannose, or 1-galactose; and that dextrohyos- 
cy amine, dextro-epinephrine, etc. are so much more potent than 
the levo forms, are full of suggestions and when understood may 
do much to clarify vital activities. 

Regarding the formation of optical bodies little is known, 
but in plants photo chemical reactions seem to play an important 
role. Cotton (Am. Chem. Phys., 1896, VII, 8, 373) found that 
the dextro and levo forms of tartaric acid absorb d. circularly 
polarized light at different rates, which suggest a method of 
their formation. 

The Action of Amino Acids in the Body 
The amino acids are utilized in the body as foods. This use 
may be in the building up of protein in the body, and repair of 
used protein. Amino acids may also be to some extent converted 
into carbohydrate and consequently into fat and will exert the 
action of these food stuffs. The following formulas show the 
possibility of carbohydrate formation from amino acids : 



COOH 

I 

CH 2 

2 | + H 2 0- 

CHNH 2 

I 

COOH 

Aspartic acid 



COOH 



CH 5 



CH 2 OH 



CeHi 2 0| 



Dextrose 



2C0 2 
/?. lactic acid 



316 CHEMICAL PHARMACOLOGY 

COOH COOH 

I I 

CH 2 > CH3 

CH 2 + HOH CH 2 OH 

! I 

CHNH 2 + HOH-+ CHOH 



COOH 
Glutamic acid 



COOH 

Glyceric acid 



Two molecules of glyceric acid forms glucose on reduction: — 
Glyceric acid-^glyceric aldehyde-^glucose 

When fed to glycosuric dogs, many amino acids, like protein, 
increase sugar excretion, and are converted into sugar. It is 
probable that carbohydrates may be used to some extent in 
the formation of amino acids, though this is not definitely prov- 
en. The only nitrogen containing carbohydrate of the body 
is glucosamine. This is found especially in chitin which forms 
the external skeleton of orthopods. It can also be prepared 
from cartilage and ovalbumin. 

Besides their function in metabolism, amino acids exert a 
specific stimulating action on metabolism. A similar action 
however is exerted by all food stuffs and is known as the specific 
dynamic action. When for example, an animal is starving and 
the energy metabolism is represented by 100 calories and we wish 
to keep the animal at this level by feeding protein, it will be 
necessary to feed 140 calories, or fat 114 calories or carbohydrate 
106 calories. The excess of heat generated above the 100 per 
cent, is the specific dynamic action. Lusk (1912) thinks that 
in the case of proteins this is due to the mass action of the 
amino acids on the cell protoplasm which they stimulate. 

The Fate of Amino Acids in the Body 

The amino acids derived from protein hydrolysis are readily 
oxidized in the body and ultimately excreted as urea, C0 2 and 
H 2 0. Stolte found that when injected intravenously into rab- 
bits, the nitrogen of glycine and leucine is almost totally excreted 
as urea, while that of alanine, cystine, aspartic acid and glutamic 



FATE OF AMINO ACIDS 



317 



acid are less readily catabolized, and phenyalanine and tyrosine 
led to no immediate urea excretion. 

Traces of unchanged amino acids may be found in the normal 
urine. The presence of glycine has been definitely established, and 
it may reach as high as 1 per cent, of the total nitrogen output. 

Tyrosine, leucine, and glycocoll are regularily found in the urine 
in cases of acute yellow atrophy of phosphorus poisoning and in 
other conditions. Cystine is found in cases of cystinuria, a 
disease of metabolism not well understood. In these cases, the 
diamines, putrescine and cadaverine, formed by putrefaction in 
the intestine may also be found. 

In the normal catabolism of the amino acids, the first step in the 
formation of urea is thought to begin with the alpha position: 

R.CH 2 CHNH 2 COOH + 2 = RCH 2 COOH + C0 2 + NH 3 

Many examples of this kind of reaction are known, e.g., leucin 
on oxidation gives iso-valeric acid 
CH 3 v 

">CH.CH 2 CHNH 2 COOH + 2 = 
CH 3 X 

CH 3 . 



CIL 



;CH.CH 2 COOH+ C0 2 + H 2 



Iso-valeric acid 



In cases of alkaptonuria tyrosin undergoes a similar change to 
form homogentisic acid 

OH HO 



CH 2 
CH.NH 2 



OH 

CH 2 +CO2+NH; 

I 
COOH 



COOH 
Tyrosin 



homogentisic acid 



318 CHEMICAL PHARMACOLOGY 

Homogentisic acid in turn is oxidized by the normal organism, 
and this may be the usual mechanism of tyrosin catabolism. In 
alkaptonuric cases homogentisic acid is either not oxidized or at 
a much slower rate than in the normal. 

Alanine is oxidized in the body as follows, 

CH 3 CH.NH 2 .COOH + -> CH 3 CHO + C0 2 + NH 3 

When oxidized in vitro by hydrogen peroxide or potassium 
permanaganate the amino group is replaced by oxygen and a 
ketonic acid is formed: 

CH 3 CH3 

I I 

H— C— NH 2 O ±=> C = 0+NH 3 

I + I 

. COOH COOH 

This reaction may be reversed by reducing agents. By reduc- 
tion of the alpha ketonic acids hydroxy acids may be formed, in 
this case lactic acid 

CH 3 
CH.OH 

COOH 

is formed, and this indirect method may explain the production 
of lactic acid in the body. Lactic acid is found chiefly in cases 
of tissue asphyxia due to excessive exercise, or deficient supply of 
oxygen. 

The reversibility of the alanine — lactic acid reaction, and the 
relation of lactic acid to carbohydrates, suggests the possibility 
of a synthesis of amino acids from carbohydrates and ammonia 
in the body. Embden obtained evidence of this synthesis by 
perfusing a liver with glycogen and found that alanine was 
formed. Many other examples of alpha ketonic acids being 
formed from alpha amino acids. It is assumed that alpha 
ketonic acids are essential products in the oxidation of alpha 
amino acids, and hydroxy acids are formed from these by reduc- 



FATE OF AMINO ACIDS 



319 



tion and are not directly derived from the amino acids (see Dakin, 
Oxidations and reductions in the animal body). 

The ultimate fate of alpha amino acids and alpha ketonic acids 
in the body is the same but, in the process of catabolism the 
ketonic acid may undergo three types of change: 

1. It may be oxidized to a lower fatty acid: 

R.CH 2 CO.COOH + O = R.CH 2 COOH + C0 2 

2. It may be reduced with formation of an hydroxy acid: 

R.CH 2 .CO.COOH+H 2 = R.CH 2 CHOH.COOH 

3. Its ammonium salt may be reduced to the corresponding 

amino acid: 

» 

R.CH 2 CO.COONH 4 +H 2 = R.CH 2 .CH.NH 2 COOH+H 2 

These three types have been imitated in vitro. 

The Fate of Alpha Amino Acids in Abnormal Conditions 

In cases of diabetes, in which there is a reduction of the ability 
of the tissues to oxidize carbohydrates, and perhaps some other 
bodies, amino acids may give rise to sugar and aceto acetic 
acid. 

The following table from Dakin (oxidations and reductions in 
the animal body) shows this: 



Increased glucose 
excretion when 
Substance given to diabetic 

animal 

Glycine -f 

Alanine + 

Valine ? ■ 

Leucine — 

Aspartic acid + 

Glutamic acid + 

Phenylalanine ? 

Tyrosine — 

Histidine + 

Lactic acid + 



Acetoacetic acid 
formation when 
perfused through 

surviving liver 



+ 



+ 



+ (?) 



320 CHEMICAL PHARMACOLOGY 

Since carbohydrates can be formed from amino acids, it follows 
that alcohols may also be formed. Their actions in the forma- 
tions of alcohols appears to be as follows: 

oxidation 
R.CH 2 .CH.NH 2 .COOH -> R.CH 2 .CO.COOH -> 

a, Ketonic acid 

reduction 
C0 2 + R.CH 2 CHO -> R.CH 2 .CH 2 OH 

Aldehyde Alcohol. 

The fate of cystine, the only sulphur containing amino acid 
is of interest since sulphur is important in pharmacology. 
In normal conditions this acid is completely oxidized and the 
sulphur eliminated in the form of sulphate. In certain individ- 
uals the ability to oxidize cystine is lacking and it appears in the 
urine. Such persons appear normal, and do not suffer from the 
condition. It is an inherited condition and is more frequent in 
males than females. The cause of this anomaly of metabolism 
is not known. 

Taurine, CH 2 .NH 2 .CH 2 S0 3 H, which is found in the bile 
combined with cholic acid, as taurocholic acid, appears to be a 
derivative of cystine or cysteine: 

COOH COOH CH 2 .NH 2 

CHNH 2 -> CH.NH 2 -> CH 2 (S0 3 H) 

Taurine. 
CH 2 (SH) CH 2 (S0 3 H) 

Cysteine Cysteic acid 

Because of the relation to the active principles of ergot, ad- 
renalin etc. the fate of tyrosine, phenylalanine and tryptophane 
are of especial interest. These are normally completely oxidized 
in the organism. This is contrary to the fact that most aromatic 
bodies are not readily oxidized. In cases of alkaptonuria 
tyrosin and phenylalanine may be converted into homogentisic 
acid: 



FATE OF AMINO ACIDS 

COOH COOH COOH 

I I I 

CHNH 2 CH 2 CH.NH : 



321 



CH ; 



CH< 



OH 



OH 

Tyrosine 



OH 



Homogentisic acid Phenyl-alanine 



The normal organism oxidizes homogentisic acid readily, but 
but alkaptonurics have not this power. 

Tryptophane. — Little is known of the mechanism of the fate 
of this body in the human organism. It apparently undergoes 
complete oxidation. When fed to dogs, it causes an increase in 
the excretion of kynurenic acid. 



CH 



/ 



HC 

II 
HC 



\ 

C- 



C.CH 2 .CHNH 2 .COOH 



CH 



NH 
CH 

Tryptophane 



HC 



CH COH 

\c/ \c. 



COOH 



\ /C\ /CH 



\/- 
CH N 

Kynurenic acid 



21 




322 CHEMICAL PHARMACOLOGY 

In this reaction an additional C atom has entered the indole 
ring. 

The fate of histidin in the body is of especial interest because 
of its relation to the active principles of ergot. When CO2 is 
split off from histidin, histamine or /3 imido azole ethyl amine, 
or ergamine is formed. 

C— NIL 

II >H 

C N^ 

CH 2 -> 

I 
CH.NH 2 CH 2 NH 2 

! 

COOH 
Histidin j3-imino azole ethyl amine 

(histamine or ergamine) 

The effects of ergamine differ in different animals. In dogs 
and cats it causes a condition resembling anaphylactic shock 
due to dilation of the peripheral vessels. While in the rabbit 
it tends to constrict the vessels. It acts directly on the vessel 
wall and may have some action on the neuro-muscular junction. 
According to some authors, histamine is the same as vasodilatin. 
Such substances as histamine, epinephrine, and perhaps many un- 
known hormones may be intermediate products in the catabolism 
of amino acids. 

POISONOUS PROTEINS 

These are protein substances, and have been termed vegetable 
agglutinins; they coagulate milk and blood. They resemble 
bacterial toxins and have been found in a number of higher plants, 
and are therefore called phytotoxins. The most important are 
Ricin — from the castor bean (Ricinus communis). Abrin, from 
the seeds of abrus precatorius — Crotin, from the seeds of croton 
tiglium. Robin from the leaves and bark of the locust, Robinia 
pseudoacacia, and Curcin from the seeds of Jastropha curcus. 
The general properties and actions of these substances are 
similar. Ricin is found in ricinus communis along with castor 



ENZYMES 323 

oil, but the oil itself does not contain ricin. It is the most power- 
ful of the phytotoxins. One thousandth of a milligram 
per- kilo is fatal to a rabbit when given hypodermically. The 
ricin agglutinates the corpuscles and also precipitates serum. 
Death occurs several days after a subcutaneous injection, with 
but few symptoms other than loss of appetite, and towards the 
end diarrhoea and vomiting. Post mortem examination shows 
congestion and inflammation of the gastro-intestinal tract with 
ecchymoses; blood in the serous cavities; punctiform hemorrhages 
beneath the serous surfaces and extravasations in various organs. 
Microscopical examination shows foci of necrosed tissue in the 
spleen, liver, intestine stomach and other organs. The whole 
picture is much the same as that caused by diphtheria -toxin. 
The poisons are eliminated through the intestinal mucosoa, which 
accounts for the great amount of gastro-intestinal injury. An 
immunity can be developed against these toxins, and antitoxins 
can be prepared. 

Abrin contains two poisons, a globulin and an albumose, of 
which the former is more powerful. Crotin is less powerful than 
ricin or abrin, but the action is similar. Robin and curcin are less 
known than the others. Curcin differs from all the others in 
having no hemagglutinative action. 

XXVIII. ENZYMES OR ORGANIC FERMENTS 

Nothing definite is known of the chemistry of enzymes. The 
word means literally "in yeast" (from the Greek "en", in; and 
"zyme", leaven. They are complex organic substances, capable 
of rendering food available for the cell. Because of their colloidal 
nature and the difficulty of obtaining enzymes in a pure condition, 
their chemical nature is unknown. They are formed within the 
living cells, although in certain cases, the cells do not secrete the 
complete enzyme, pro-ferments or zymogens, which are trans- 
formed into active enzymes outside of the cell, being first formed. 

Enzymes differ from catalysts in their sensitivity to heat and 
light. All enzymes are destroyed at 100°C. and most of them at 
60° C. Each enzyme acts best at a definite temperature which is 
the optimum temperature. For the digestive enzymes this is 
about 40°C. The destructive action of heat is perhaps due to a 
coagulation of the proteins of the enzyme. 



324 CHEMICAL PHARMACOLOGY 

Regarding light, there seems to be two kinds of action: 

(a) Those produced by ordinary light in presence of oxygen. 
This is greatly accelerated by the presence of fluorescent sub- 
stances such as eosin, quinoline red etc., which though not under- 
stood yet offers hope of therapeutic value in many diseases. 

(6) Ultra-violet light independent of oxygen destroys diastase 
and other enzymes. In this connection we might add that 
various rays of light and emanations are now used with consider- 
able effect in cancer and other diseases the causes of which are 
unknown. 

The colloidal nature of enzymes is shown by lack of diffusibility 
and by their precipitation by other colloids. Enzymes are 
adsorped readily by many finely divided inert particles such as 
charcoal, infusorial earth, etc. This adsorption is a phase of 
precipitation, and in this case is electrical. 

The addition of salts, drugs, etc. influence enzyme action; 
those substances hastening it being called accelerators, those 
depressing it being called depressants or paralysers. 

If enzymes are injected subcutaneously into an animal, an 
antienzyme may be formed, which neutralizes the activity of an 
enzyme in a manner similar to toxin and antitoxin. 

ENZYMES USED AS MEDICINES 

The digestive ferments diastase, pepsin, and trypsin have been 
used to some extent in medicine. The value of these in most 
cases is questionable, for the reason that it is doubtful if defici- 
ency of the natural digestive enzymes ever occurs. The term 
" Amylaceous dyspepsia" has been used to indicate cases of 
dyspepsia supposedly due to incomplete digestion of starches. 
However, for all practical purposes, starches are digested in the 
intestine, and it has never been shown that there is any deficiency 
of the diastatic intestinal ferments. Diastase preparations as 
medicines would therefore seem superfluous. The pepsin of the 
stomach is almost always capable of digesting proteins, providing 
the reaction is acid, and the deficiency is not in pepsin but a lack 
of acid. The treatment therefore, except in rare cases, is acid 
medication not the administration of pepsin. However, while 
pepsin in the majority of cases is superfluous it is not injurious. 

Pancreatic Fermenjs. — The value of these in medicine is even 
more problematical than pepsin. When given they are adminis- 



FATE OF ENZYMES 325 

tered in a capsule or in a salol coated pill, to avoid digestion in 
the stomach. To get such preparations through the stomach 
without digestion, and at the same time, have them in a form 
that will be liberated in the intestine is very difficult. It is 
doubtful if any of the preparations that pass through the stomach 
undigested are liberated in the intestine. If they are not liber- 
ated they are useless, and if liberated, superfluous. 

THE FATE OF ENZYMES IN THE BODY 

Since the chemistry of the enzymes is unknown, the exact fate 
cannot be determined. The protein part, or impurity, suffers 
the fate of all protein in the body. The enzymes may be used 
over again in the body to some extent. They are also excreted 
in the urine and faeces. 

Under hydrolytic enzymes, we find a group of fat-splitting 
enzymes called lipases or steapsins. This group was found by 
Green (1890) and subsequently' confirmed by Connstein, Hoyer, 
and Wartenberg, who found that castor-oil seeds contain an 
enzyme that hydrolyses the fats present. In the* tissues of the 
body, this fat-splitting role of lipase which brings about the 
separation of neutral fat in the presence of an excess of water is 
reversible and builds up fat, when allowed to act upon a mixture 
of fatty acids and glycerol in a medium poor in water. Diastase, 
which hydrolyses starch to maltose and dextrose, is one of the 
commonest of enzymes, and occurs in practically all living matter. 

Under fermenting enzymes may be mentioned the alcoholic 
fermentation of glucose, levulose, mannose, etc., by zymase, 
which probably occurs also in animal tissues, this supposition, 
however, requires more evidence than has yet been shown. It 
is thought that traces of alcohol found in the blood may have 
been formed in the intestine by bacterial action. 

Coagulating enzymes, are represented by rennin, which curdles 
milk; thrombin, which coagulates blood; and pectase, which coagu- 
lates soluble pectic bodies. 

The oxidizing enzymes are divided into (a) those which oxidize 
alcohols to acids, and (b) those which set free oxygen from hydro- 
gen peroxide or other peroxides. These are the peroxidases or 
catalases. 

Life processes of all kinds are accompanied by enzyme action. 



326 



CHEMICAL PHAEMACOLOGY 



Growth, repair, ripening of fruit, decomposition, etc., have been 
explained by enzyme activity. Enzymes are not held to originate 
an action, but simply to accelerate those already in progress. 
Whether the facts justify this opinion remains to be determined. 

Enzymes are classified according to the substance acted on as 
follows : 

Coagulating enzymes (thrombin rennet). 

Pepsin, trypsins, erepsins, amidases, catalases, etc. 

The most important are arranged in tabular form as follows : 



Feements Acting on Carbohydrates 



Name of Enzyme 


Substances on which 


Products of the 




Enzyme acts. 


reaction 


Invertin or sucrase 


Cane sugar 


Dextrose and levulose 


Amylase or diastase 


Starch and dextrins 


Maltose 


Glucase or maltase 


Dextrins and maltose 


Dextrose 


Lactase 


Lactose mycose or 


Dextrose and galactose 


Trehalase 


Trehalose 


Glucose 


Cytase 


Hemi-cellulose 


Mannose and galactose 


Pectase 


Pectin 


Pectates and sugars, ara- 
binose 


Caroubinase 


Caroubin 


Caroubinose 


Invertase which hydro- 


Raffinose to 


Levulose and melibiose 


pses 






Maltase which hydro- 






pses 


Maltose (malt sugar) 


Dextrose 


Inulase which hydro- 






lyses 


Inulin to 


Levulose 



Ferments Acting on Fatty Substances 

Steapsin or lipase | Fatty substances | Glycerin and fatty acids 

Ferments Acting on Glucosides 



Emulsin 



Myrosin 
Betulase 
Phytase 



Amygdalin and 
glucosides 



other 



Potassium myronate 



Gaulthcrin 



Phytin 



Glucose, oil of bitter al- 
monds, and hydrocy- 
anic acid 

Glucose and allyl iso- 
sulphocyanate 

Oil of wintergreen 

Glucose 

Inosite and phosphoric 
acid 



FERMENTS 
Ferments Acting on Proteins. — Continued 



327 



Name of Enzyme 



Substance on which 
Enzyme acts 



Products of the 
reaction 



Ferments Acting on Proteins 



Rennet 



Plasmase 
Pepsin 
Trypsin 
Trypsin 

Papain 



Caseinogen 

(Casein, Hammarsten) 
Fibrinogen 

Albuminoid substances 
Albuminoid substances 
Albuminoid substances 

Albuminoid substances 



Casein 

(Para casein) 
Fibrin 

Proteoses, peptones 
Proteoses, peptones 
Polypeptides and amido 
acids 
Polypeptides and amido 
acids 
Erepsin contained in the intestine which hydrolyses 

Proteins to Polypeptides and amino 

acids' 
Bromelin contained in the pineapple juice which hydrolyses 



Proteins to 



Polypeptides and amino 
acids 



Zymase or alcoholic di 
astase 

Lactic acid bacteria 
Butyric bacteria, etc. 



Ferments Causing — Molecular Decomposition 

Starches. Alcohol and 
carbonic acid. Vari- 
ous sugars C0 2 lactic 

Lactose acid etc. 

Lactose Butyric acid 



Ferments Acting on Proteins to Cause Clotting 



Rennin (Chymosin) 

Thrombin 

Pectase 

Laccase 
Oxidin 



Malase 

Tyrosinase 

Oenoxidase 

Oxidases which oxidize 



which curdles milk 
which coagulates blood 
which coagulates soluble 

pectic bodies 
Uruschic acid 
Tannin, anilin, etc. 
Coloring matters of 

cereals 
Coloring 

fruits 
Tyrosine 



matters of 



Coloring matter of wine 
alcohols to 



Oxyuruschic acid 
Unknown products of 
oxidation 

Unknown^ products of 

oxidation 
CO2 parahydroxy ethyl- 

amine, NH 3 etc. 
C0 2 parahydroxy ethyl- 

amine NH 3 etc. 
acids e.g., action of My- 

coderma aceti, etc. 



328 CHEMICAL PHARMACOLOGY 

Ferments Acting on Proteins. — Continued 



Name of Enzyme 


Substance on which 
Enzyme acts 


Products of the 
reaction 


Ferments Acting on Urea 


Urease 


Urea 
Deamidizing Enzymes 


Ammonia and CO2 


Nuclease 


Splits nucleic acid 


Purin bases, etc. 


Guanase 


Converts guanine 


Xanthine 


Adenase 


Converts adenine 
Oxidizing Ferments 


Hypoxanthine 


Oxidases 


Causes oxidation of or- 
ganic substances 






Decomposes hydrogen 


Water, oxygen 


Catalase 


peroxide 





XXIX. CHLOROPHYLL 

Chlorophyll (Gr. chloros, green — phyllon, leaf) . Plant colors 
have no physiological action and if used in medicine, it is for 
their esthetic or psychic effect. But the relation between chlor- 
ophyll and hemoglobin is of great biological significance. 

The name chlorophyll was first applied by Pelletier and Caven- 
tou to the green coloring matter of plants. By the use of the 
spectroscope it has been found that chlorophyll of the green leaf 
instead of being one simple color, contains at least seven different 
pigments. 

The reactions in the formation of chlorophyll are not well 
understood. Light is essential. The presence of iron and mag- 
nesium is necessary. Starch and sugar may or may not be 
essential. This point is still under investigation; as is also 
the chemistry of the substances which immediately precede 
chlorophyll and from which it is formed. Lecithins and proteins 
seem to take part in its formation. The chemistry is complex 
and not definitely known, but is sufficiently understood to 
show a definite chemical relationship between chlorophyll and 
hemoglobin. 



CHLOKOPHYLL 329 

RELATIONSHIP OF CHLOROPHYLLS AND HEMOGLOBINS 

There are several different chlorophylls, just as there are dif- 
ferent hemoglobins. The hemoglobin of different animals varies 
slightly in composition but all are closely related chemically. 

By the action of glacial phosphoric acid containing HI on 
hematin or hemochromogen, haemopyrrol, C 8 Hi 3 N, a colorless 
oil which in air gradually changes to urobilin is formed. Uro- 
bilin is also produced by the action of the same reducing agents 
on the chlorophyll derivative, phyllocyanin. This shows a close 
relationship between chlorophyll and haemoglobin. 

There are two well known chlorophylls: 

,COOCH 3 

Chlorophyll (a) C 32 H 29 N 3 Mg^ -COOC 20 H 39 

NET 

XJOOCH, 

and chlorophyll (b) C^^sO^NMg^ 

COOC2()H 3 9 

(Willstatter and Isler) 

When these are treated with alkalies, two groups of products are 
formed : 

1. Phyllins, which contains magnesium and 

2. Porphyrins, which are free from magnesium. 

On oxidation with chromic and sulphuric acid, Marchlewski, also 

C Cv 

Willstatter and Asahina, think the pyrrol group ^ N 

C (X 

exists in the chlorophyll molecule since the pyridine derivatives 

CH 3 .C COv 

^NH Hsematinic acid imide, and 
COOH.CH 2 . CH 2 C-^C(r 

CH 3 .C CO. 

.NH Methylethylamaleinimide are formed. 
CH 3 . CH 2 C— CO X 

CH 3 .C.COOH 
Haematinic acid has been obtained 

COOH.CH 2 .CH 2 .C COOH 



330 



CHEMICAL PHARMACOLOGY 



from hemoglobin and the imide of this obtained from chlor- 
ophyll again establishes a relationship between chlorophyll and 
hemoglobin. Hematin and hsematoporphyrin also yield hse- 
matinic acid imide. 

Pyrrol is an important nucleus in many biological compounds, 
being found in alkaloids, nicotine, cocaine, and others, and 
in proteins. In fact, proteins may be looked upon as containing 
an alkaloidal nucleus. 

The structure of the pyrrol derivatives is indicated as follows : 

0) HC C H (0 



a) 



HC 



C H (a 



NH 



Besides these mentioned, the following derivatives of hsematin 
are of biological importance. 



CH- 



(I) 
C C C2H5 



(II) 

CH3 — C C — C2H5 



CH,. C 



CH 



NH 

Isohemopyrrol 
0-ethyl a' 0' dimethyl pyrrol 

(III) 
CH 3 . C C C 2 H 5 



C CH 3 



CH< 



NH 

Kryptopyrrol or a 
methyl ethyl 0- 
methyl pyrrol 
(IV) 
C C CH 2 .CH 2 .COOH 



CH- 



C CH- 



NH 

Phyllo pyrrol or a methyl 
0-ethyl a 0' dimethyl 
pyrrol 



NH 



Isophonopyrrol carboxylic acid 
or 0-propionic acid a' 0' 
dimethyl pyrrol. 

The bile acids are derivatives of hemoglobin and also contain 
pyrrol nuclei which are derived from the hematin of blood. When 
blood is dropped into acetic acid containing some NaCl and the 
solution heated to 95°C. the hydrochloride of haematin, hsemin 



COLORING MATTERS 331 

C 3 3H320 4 N4FeCl, crystallizes out. When haemin is treated 
with HBr, a dibrom compound is formed and iron is lost. When 
the dibrom compound is hydrolysed hsemato porphyrin is formed 
which is a dibasic acid of the formula : 

/OH 

c 3 iH 3 4N 4 ^: COOH 



x COOH 
Hematoporphyrin 
The intermediate reaction is not known. When hematophyrin 
is reduced by heating with methyl alcoholic potassium hydroxide 
in pyridine solution, hemoporphyrin C33H36O4N4 is formed, which 
on heating with soda lime forms aetioporphyrin C31H36N4. 
Willstatter thinks this is the mother substance from which both 
chlorophyll and hematin are derived. 

HC=CH 



OH3 ■ — C— CH-x 

!! /N 

C2H5 — C — CL 

• )c 

C2H 5 — C- — Cv 

)NH 


c-c 

n( II 

^C— CH 
C \ 


• 


ch 3 — c=c/ 

X CH 3 


X C=C— CH 3 

1 
CH 3 




Aetioporphyrin. 






HC=CH 

1 1 




CH 3 — C-CH V 


1 1 




II >N 
C2H5 C — CL 


< II 

)c~CH 

°\ 

/C=C— CH 2 - 




CH 2 — CH 2 — C=C<^ 
1 /NH 


-CH 2 

| 


HOOC CH 3 — C=c/ 


X C=C— CH 3 


COOH 



CH 3 CH 3 

Hsemoporphyrin. 



332 CHEMICAL PHARMACOLOGY 

The following skeleton formulae has been suggested by Werner 
to show the relationship between chlorophyll and hsematin. 



:N 



Mg 




)N N 

Chlorophyll 

In addition to chlorophyll plants contain many other related 
pigments such as carotin, the yellowish red pigment of carrots, 
which is found with chlorophyll in many plants. It has the 
molecular formula C 4 oH 5 6. Xanthophyll C40H56O2 and carotin, 
both neutral substances, are closely 1 elated and on reduction 
xanthophyll can be converted into carotin. Tucoxanthin 
C40H54O6 isolated from brown algae has basic properties and forms 
blue salts with HC1 and H 2 S0 4 . 

Besides the colors mentioned, there are yellow colors known 
as flavones and xanthones as. well as anthocyanin, which give 
blue, red, and violet tints ; and many others, which have as yet 
only a remote interest in the chemistry of drugs. Chlorophyll is 
the only one that has been investigated in detail. 

While chlorophyll and hemoglobin are related chemically, 
their functions are quite dissimilar. The chief function of hemo- 
globin is as a carrier of oxygen, while chlorophyll participates in 
both metabolism and assimilation. Chlorophyll contains no 
iron, while the main function of hemoglobin depends on this 
element. 

The following diagram shows the relationship of chlorophyll, 
hemoglobin and bile pigment (after Mathews, p. 423) : 

The great difference between plants and animals is that in the 
plant, reduction and synthesis are the predominant chemical 
processes, while in the animal, oxidation and hydrolysis predomi- 
nate. 



HEMOGLOBIN 



333 



II. 



Hemoglobin 



III. 

Chlorophyll 

i 

Phyllocyanin 



* 



Globin Hematin 

C 32 H 3 2N 4 3 Fe(?) 

I 
Hematoporphyrin Bilirubin Phylloporphyrin 

C 32 H 36 N 4 6 (?) C 32 H 36 N 4 6 (?) C 32 H 36 N 4 2 



1 
Biliverdin 

C 32 H 3 6N 4 8 

1 
Urobilin 
C 32 H 40 N4O 7 (?) 



Hemopyrrols Hemopyrrols Hemopyrrols 

C 8 H 13 N (etc..) C 8 H 13 N (etc.) C 8 H 13 N (etc.) 

\ 1 / 

Hematic acids 
C 8 H 8 5 C 7 H 9 N0 2 C 8 H 9 N0 4 

The Fate of Chlorophyll in the Body 

We known nothing definitely about the transformations of 
chlorophyll in the alimentary tract. Neither chlorophyll nor 
hsematin are absolutely essential in the diet, since the animal 
body is apparently able to construct respiratory pigments from 
the split products of protein. Those containing the pyrrol ring 
are probably used in this synthesis. 



Other Plant Colors 

Litmus results from the fermentation of the CH- 

lichens Rocella and Lecanora. These lichens con- 
tain orcinol, partly free and partly as orsellic 
acid and combinations. By special treatment 
with ammonia and potassium carbonate, litmus 
is formed. The concentrated salt mixed with Orcinol 



OH 



OH 



334 CHEMICAL PHARMACOLOGY 

chalk or gypsum, constitutes commercial litmus. Little is known 
of the chemistry of this substance, which contains several colors, 
azolitmin, erythrolitmin, and erythrolein. The first named is the 
most important and is soluble in water, but insoluble in alcohol. 
The. others are insoluble in water and soluble in alcohol. When 
orcinol is exposed to the air and ammonia it changes to orcein, 
C28H24N2O7, which is a reddish brown amorphous powder, the 
chief constituent of archil, which is also known as cudbear or 
persio. It is sometimes used to color medicines. 

Curcumin, curcuma, Ci 4 Hi 4 4 or tumeric is the coloring prin- 
ciple in the root of curcuma longa. It dissolves in alkalies to 
form brownish red salts. 

Hemotoxylin Ci 6 H ]4 6 + 3 H 2 is the coloring matter of 
logwood, sometimes used in medicine for its astringent effects. 
It reduces Fehling's solution, dissolves in alkalies with a violet 
color (and therefore may be used as an indicator). When fused 
with KOH it yields pyrogallic acid and resorcinol. 

Red saunders is the heart wood of pterocarpus santalinus. 
When extracted with alcohol, it gives a red solution and is used to 
color the compound tincture of lavender. 

Coccus (cochineal) is the coloring matter of the cochineal bug. 
Besides its use in pharmacy, it is particularly valuable in chemis- 
try as an indicator and is employed especially in the titration of 
ammonia and the carbonates. 

Carmine is prepared by extracting the cochineal with water 
and precipitating with alum and lime or cream of tartar. 

Crocus or saffron is made of the stigmas of crocus sativa. 

Caramel is partly burnt sugar. 

Annato is the pulp sunounding the seeds of Bixa Orallana, a 
South American Plant. Annato and saffron are also used to 
color butter and oleomargarin. 

Alkanet is the root of alkanna tinctoria. This is red with acids 
and blue with alkalies. 

Indicane C 7 H6NCOC 6 Hii05 is a glucoside found in a number of 
plants, as indigo fera anil 
I. arrecta 
I. tinctoria 

I. summatrana and many other plants. When boiled 
with a mineral acid, indicane breaks up into glucose and indoxyl. 



INDICAN 335 

COH 
C 7 H 6 NCOC 6 Hu05 = C 6 H 12 6 + C 6 H 4 ( ^CH 

X NH X 

Indican Indoxyl 

When indoxyl is exposed to the air it is oxidized and gives a 
deep blue coloring matter indigo 

/ co \ ' / co \ 

C6H4V ,0 : Cv ,kjqxLi 

X NH X X NH X 

Indigo blue 

It was formerly supposed that plant indican was identical with 
urine indican the latter being so named, because of this supposed 
identity. The two are not identical, however, although both 
may give rise to indoxyl; plant indican through hydrolysis, and 
urinary indican by oxidation of indol. 

/ CH \ . ... 

Indol C 6 H/ \CH is also formed in the intestine as the 

X NIF 
result of putrefaction. It is oxidized most probably in the liver 
to indoxyl and this is eliminated as the potassium sulphuric ester. 
C(OS0 2 OK) 

/ \ 

C 6 H 4 ^ y CH. This ester is known as urine indican 

\ / and on oxidation gives indigo blue and 

^NH acid potassium sulphate. 



XXX. COLLOIDS 

In all reactions of chemical pharmacology, one of the reacting 
bodies is a colloid. The word colloid was first applied to 
bodies that had the properties of glue (Gr. kolla, glue; eidos, 
appearance). More recent study has widened the original 
scope of this word. Graham, in 1861, divided substances into 
crystalloids and colloids, classifying them on the following 
basis; those substances that would diffuse through an animal 
membrane or parchment paper he called crystalloids, and those 
that would not do so, colloids. Sodium chloride, sugar, alka- 



336 CHEMICAL PHARMACOLOGY 

loidal salts and the like are crystalloids, while gums, starches, 
resins and proteins are colloids. 

Besides the property of non-diffusion through membranes, 
colloids are amorphous, viscous, and when sufficiently concen- 
trated, form gels. The pseudo solution of the colloid to distin- 
guish it from a true solution is called a sol. According to the 
liquid in which the colloid is suspended (water, alcohol, etc.) the 
sol is called hydrosol, alcosol, and the gel, hydrogel, alcogel. 

Graham also found that under some conditions, non-colloidal 
matter might become colloidal. He discovered that by adding 
an excess of dilute hydrochloric acid to a dilute solution of sodium 
silicate he obtained a clear solution instead of a precipitate of 
silicic acid. When such a solution was dialyzed, the sodium chlor- 
ide was washed out and the ordinarily insoluble silicic acid 
remained in a colloidal condition. A similar method is used at 
present to prepare colloidal iron. 

Colloidal matter under some conditions can also be crystallized; 
hemoglobin and egg albumen have been obtained in crystalline 
form. At the present time, therefore, the opinion is that the 
colloidal condition is not entirely due to the kind of matter, but 
also to the condition under which the matter is found, and the 
size of the particles. In proper solvents, perhaps any form of 
matter may be amorphous or crystalline. Even such a typical 
crystalloid as sodium chloride in benzene may be colloidal, while 
under other conditions the typical colloid, albumen, may be 
crystalline. These extreme cases, however, should not minimize 
the difference between crystalloids and colloids as they are found 
in nature. 

CHARACTER, OR NATURE, OF COLLOIDS 

Enzymes are colloids, and the study of artificial enzymes has 
done much to explain the nature of colloids. Bredig found that 
if an electric spark produced by a current of 8-12 amperes at 30 
to 40 volts is passed through pure water between two platinum 
wire electrodes, the metal disintegrates and the water becomes 
first, yellow, and then a brown or black color. The liquid filters 
easily, no particles are visible under the microscope, and ap- 
parently the platinum has gone into solution. The physical 
constants, however, do not show a true solution. The freezing 



COLLOIDS 337 

point, boiling point, or osmotic pressure is but little changed, 
whereas if an equivalent quantity of a salt is added, these constants 
are definitely changed. Instead of being in true solution, the 
platinum is in a pseudo solution or a state of extreme division 
(dispersion) that -may be seen by the aid of the ultra microscope. 
The size of these particles has been estimated at 0.00001 milli- 
metre. These particles in colloidal solutions are known as the 
disperse phase of the colloidal solution. The water is the con- 
tinuous phase. Gold, silver, copper, and other metals have been 
prepared in pseudo solution. These solutions, when allowed to 
stand, do not respond to the laws of gravitation; the solution is 
rather permanent, due to the fact that the particles carry an 
electric charge. The evidence to support the theory that the 
particles are changed electrically is: 

1. The method of preparation. The current that causes the 
disintegration of the metal, and carries it into solution, would 
probably remain on it. 

2. The particles will wander in the stream if a current of electri- 
city is led through the solution. 

3. Electrolytes will precipitate colloids. This is well shown by 
the action of Na2S0 4 or MgS0 4 on the colloidal iron, or by the 
action of HC1 on colloidal arsenic sulphide and by the fact that 
colloidal platinum can not be kept for any length of time if 
electrolytes are present in the water. 

4. Colloids of opposite electrical sign precipitate each other. 
Practical application is made of this in the use of aluminum 
cream Al(OH) 3 and colloidal iron, Fe(OH) 3 to precipitate the 
proteins of blood, in blood sugar determinations. 

5. Non-electrolytes such as sugar will not precipitate colloids 
in water solution. Alcohol, however, which is also a non-electro- 
lyte will cause precipitation but this is due to a changed solvent. 

The chief electro-negative colloids are arsenious sulphide, 
antimony sulphide, gold, copper, and nearly all metals, as well as 
most proteins, in neutral or slightly alkaline solution, lecithin 
and phosphatides, the carbohydrates, gum, starch and glycogen, 
and nucleic acid and soaps. 

The electro-positive colloids are ferric hydrate, aluminum 
hydrate, basic proteins, histones and protamines, proteins in acid 
solution, and oxyhemoglobin. 

22 



338 CHEMICAL PHARMACOLOGY 

Classification. — The colloidal solution of a metal like platinum 
is vastly different in viscosity from a solution of gum on protein. 
The classification of colloids, which is based mainly on this dif- 
ference of viscosity of their solutions, is as follows : 

1. Suspensoids, or inorganic. 

2. Emulsoids, or organic. 

As the names indicate, suspensoid colloids resemble a suspen- 
sion of solid matter in a liquid, while emulsoids resemble emul- 
sions. Colloids differ from simple suspensions or emulsions in 
being charged electrically. The particles of colloid all bear the 
same kind of electricity, hence repel each other. This keeps them 
in solution. The electrical charge also acts against the force of 
gravity, and there is but little tendency to form a deposit or 
precipitate until the charge is neutralized. Only inorganic col- 
loids belong to the suspensoid class. They may be prepared first, 
by the use of an appropriate electric current under water, or, 
second, by the reduction of dilute solution of metals by reducing 
agents such as formaldehyde, third, when hydrogen sulphide is 
passed through a solution of arsenious acid, arsenic trisulphide 
may remain in colloidal solution. Some other metals act in the 
same way. Some of the suspensoid colloids are used in medicine. 

Colloidal preparations of silver are used in medicine especially 
in the treatment or prevention of gonococcus infections of the 
eye and mucous membranes. Colloidal gold is employed as a 
diagnostic aid in syphilis, tuberculosis, etc. Copper has been 
advocated in the treatment of carcinoma, etc. Platinum, in 
the form of platinum black, has been used to a considerable ex- 
tent by laboiatory workers. The chief suspensoid colloids are: 

Fe.Ag. 

colloidal metals — Cu.Au. 

Pt.Al. 

kaolin, antimony sulphide, arsenious sulphide. 

DIFFERENCES BETWEEN THE SUSPENSOID AND EMULSOID 

COLLOIDS 

The emulsoid colloids make up the greater part of living ma- 
terial. They are solutions of a liquid in a liquid; in other words, 
the disperse phase as well as the solution is liquid. This ac- 



COLLOIDS 339 

counts for their having a greater viscosity than suspensoids. 
Solutions of liquids in liquids have no sharp boundary lines as 
might be expected between solids and liquids, and they have 
little, if any, electrical properties. When free from electrolytes, 
they do not travel with the electric current, and are not as sus- 
ceptible to electrolytes as suspensoids, which are precipitated by 
traces of electrolytes. Emulsoids are precipitated only after 
the addition of considerable quantities of electrolytes. Traces 
of electrolytes seem to aid fluid solution, presumably by adding 
their charge to the colloid. 

Emulsoids are precipitated by suspensoids. Colloidal iron 
has been used for this purpose to remove the blood proteins in 
blood sugar analysis. The excess of the suspensoid is removed 
at the same time by the addition of an electrolyte like MgS04 
or Na2S04- However, where there are large amounts of emul- 
soid present, it forms a coating on the suspensoid particles and 
prevents their complete precipitation by the electrolytes. This 
is the chief objection to this method for blood-sugar work. 

The difference between emulsoid and suspensoid colloids is 
probably due to a difference in the affinity of the two substances 
for the solvent. Suspensoids have practically no affinity for 
the solvent, and readily fall out of solution when their electric 
charges are removed. Emulsoid colloids which are hydrophyljc 
require an excess of the neutralizing salt to overcome the union 
of the colloid and the water. Such colloids are called hydro- 
phyl because they have an affinity for water. This is strikingly 
illustrated in the change of viscosity in water caused by a small 
amount of colloid. A 1 per cent gelatine increases the viscosity 
of water 29 per cent. 

GEL FORMATION 

In an ordinary solution of an emulsoid colloid, the solvent or 
water is the continuous phase. It is possible to think of a small 
body going through the solution, passing around the isolated or 
dispersed particles as a ship would sail around small islands. 
When these colloids gel, a molecular arrangement of the disperse 
phase takes place, and a network is formed. The water now 
appears to be the disperse phase, as it is enmeshed in a cellular 
network of colloid. One could think of a body being able to 
pass along the network from any portion of it to any other over 



340 CHEMICAL PHARMACOLOGY 

a continuous route. This netlike structure can be substantiated 
by the use of the microscope. 

When gelling occurs, the colloid acts more like a solid than a 
liquid. Gelatin and agar-agar form gels readily, but on heating 
they will liquefy, and again, on cooling, set or gel. Such sub- 
stances are called reversible gels. Protoplasm, on heating, forms 
an irreversible gel. If a gelatin or agar gel is allowed to stand 
for some time, it contracts and some water is liberated. This proc- 
ess of contraction with the liberation of liquid is called syneresis. 
Blood, on clotting, may show the same phenomenon, which is 
well known in the preparation of bacterial media also. This 
phenomenon may be of great importance in pharmacology. The 
water holding capacity of protoplasm is changed in a similar 
way, and the diuresis following the administration of alkalies 
and salts has been explained on such a basis. It is well known 
that the water holding capacity of gelatin and fibrin is modified 
enormously by the presence of salts. 

LYOTROPE SERIES 

Colloids, according to the affinity of the disperse phase for the 
dispersing medium may be classified as lyophile, where there is 
a marked affinity of the disperse phase and the medium and 
lyophobe, where no such affinity, is shown. When water is the 
dispersing medium, the terms hydrophile and hydrophobe are 
also used. 

In the lyophobe series, which is synonymous with suspensoid, 
the physical properties of the sol are very little different from 
those of the dispersing medium, while the physical properties 
of the lyophile markedly change those of the medium. Much 
greater concentrations of electrolytes are necessary to precipi- 
tate the lyophile series of colloids. According to Pauli, both 
ions of an electrolyte play a role in the precipitation of colloids. 
While one ion precipitates, the other may have a solvent effect. 
Cations as a rule act as precipitants, while anions are solvents, 
the total action being the algebraic sum of these actions. From a 
scries of experiments, the relative efficiency of the ions in causing 
precipitation, etc., has been arranged from the least to the most 
effective. This series is known as the lyotropic series. The 
following table shows the relative action of the various ions. 



COLLOIDS 341 

Kations— Mg NH 4 K Na Li 

Anions 

Fluoride + + + 

Sulphate.. ' + + + + + 

Phosphate + + + 

Citrate + + + 

Tartrate + + + 

Acetate — — + + 

Chloride - - + + + ' 

Nitrate - — - + + 

The action of the ions in this series is so nearly the same se- 
quence in many other reactions in which they can react only 
indirectly that their action in most cases is thought to be on the 
solvent or dispersing medium rather than on the colloid. The 
sequence does not follow any chemical order as valence, atomic 
weight, or the like; for example, 

1. In the hydrolyses of esters by acids, 
anions S0 4 < (H 2 0)< Cl< Br 
kations H 2 0< Li < Na< K < Rb <Cs 

In this case, S0 4 retards action, in all others the ions accelerate. 

2. In the hydrolyses of esters by bases, 
anions I > N0 3 > Br > Cl> H 2 0<S0 4 
kations Cs > Rb > K > Li H 2 

It is seen here that the ions that accelerated the acid hydrolysis 
retard basic hydrolysis. 

3. The surface tension of aqueous solutions, 
H 2 < I < N0 3 <C1 < S0 4 <C0 3 

All these ions increase surface tension. A similar influence is 
exerted on viscosity. 

ELECTRIC CONDITIONS OF COLLOIDS 

As we have seen, there are various reasons for believing that 
colloids are electrically charged: (1) they migrate in an electric 
current; (2) oppositely charged colloids precipitate each other. 

The proteins are amphoteric, but are more acid than basic. 
The isoelectric point, i.e., the reaction in which they will not 
migrate in the electric current, is: 



342 CHEMICAL PHARMACOLOGY 

PH 

Serum albumin 4.7 

serum globulin 5.4 

casein 4.7 

oxyhemoglobin 6 . 74 

It may be that all colloids to some degree at least are amphoteric. 
PROTECTIVE POWER OF COLLOIDS 

The presence of colloids in a solution greatly lessens the action 
of electrolytes. Suspensoid colloids are also protected by the 
presence of emulsoid colloids of the same sign; suspensoids mixed 
with emulsoids can be evaporated to dryness and the residue 
redissolved in water. Without the emulsoid, the colloidal nature 
of the suspensoid would be destroyed. Colloidal mercury and 
silver can be made more stable by admixture with emulsoid 
colloids. This protective power is used in medicine to disguise or 
lessen the taste of acid and bitter medicines. Solutions of gly- 
cyrrhizae, acacia, etc., are used as vehicles because of this pro- 
tective action on the nerves of taste. 

CHANGE IN COLLOIDS IN GEL FORMATION AND PRECIPITATION 

Just as there is no sharp line between crystalloids and colloids 
so there is no sharp line between pharmaceutical emulsions and 
emulsoid colloids. The emulsions of the pharmacist are, perhaps, 
electrically charged to some extent, and this helps to hold them 
in solution. The emulsifying agents used are usually gum 
acacia or tragacanth which produce very viscous solutions which 
settle very slowly. The magma of magnesia which is mainly 
magnesium hydroxide resembles colloidal iron or iron hydrate. 
Under a variety of conditions, all emulsions or emulsoid colloids 
" crack" or precipitate. The cause of these changes may be: 
(1) spontaneous; (2) heat or cold; (3) changes in the volume or 
composition of the solvent; (4) the action of enzymes; (5) other 
colloids; (6) electrolytes. 

1. Spontaneous change. Just as any electrically charged 
body may lose its charge and become neutral, so a colloidal solu- 
tion after a time may crystallize, precipitate, or otherwise lose its 
colloidal character. 



SURFACE TENSION. 343 

2. Cold is especially liable to destroy pharmaceutical emul- 
sions. Emulsoid colloids are also less stable on freezing. Heat 
above the coagulative point of an emulsoid coagulates it. Heat 
will also demagnetize iron. - 

3. The effect of changes in the volume of a solvent is well 
illustrated when a dilute solution of gelatin or agar is evaporated 
to a small volume. It gels. If the solution is changed by 
adding alcohol, the gelatin or agar is precipitated, in the first 
instance there is no intramolecular change other than the abstrac- 
tion of water and when this is again added, the emulsoid character 
is restored. In such a case, the change is reversible. In the 
second there is an intramolecular change aside from the changes 
in the solvent and this change is irreversible. 

4. The action of enzymes. The clotting of blood and the 
curdling of milk are types of irreversible gel formation. The 
mechanisms of these actions are not well understood, but are due 
to an electrical neutralization of the colloids, in all probability. 

5. Suspensoid colloids are especially susceptible to the action 
of electrolytes. The action here is due to the neutralization of 
the charges on the suspensoid by the electrolyte. Emulsoids are 
but little influenced by small amounts of electrolytes, due to their 
characteristics being less well defined, but are precipitated by- 
larger amounts of the salts. That the electrical charge of the 
emulsoid plays some part in the precipitation is seen in the series 
of effectiveness of the anions in the salting out of non-electrolytes. 

SURFACE TENSION 

A substance in a gaseous state tends to increase its volume, 
while substances in the liquid state tend to contract into the 
smallest volume, or volume with the least surface area. The 
surface in this condition, in all liquids behaves as if stretched. 
This stretch or pull on the surface film is the result of unbalanced 
molecular forces. In any liquid the molecules have a definite 
attraction for each other. This attraction has been estimated at 
10,000 to 25,000 atmospheres. A molecule in the center is sub- 
ject to the same force from all sides, and consequently there is 
no movement one way or the other. Below the surface layer, 
the molecules exert an attraction for those above them in the 
surface layer, while those on the top are not attracted by the 



344 CHEMICAL PHARMACOLOGY 

atmospheric gases, and bend or curve in the direction of the pull 
from within, hence tend to assume the spherical form. The 
thickness of this film, or the range of the molecular attraction 
has been estimated at about 6 X 10~ 8 millimetres. 

This stretch or pull on the surface layer interferes with the 
movements of the molecules, and for this reason confers on the 
liquid some of the properties of a solid, since in the solid state, 
freedom of movement in the molecules is limited. Various meth- 
ods have been devised to measure surface tension, the most 
practical being the following. The average weight of a drop of 
the fluid falling from a standardized pipette or stalagmometer is 
taken. The surface tension of water is considered as unity, and 
that of any other fluid, like blood or serum, is calculated by di- 
viding the weight of the liquid by the number of drops, and com- 
paring this with water under the same conditions. 

Surface tension of liquid = sp. gravity of solution multiplied 

by number of drops of water 

number of drops of solution 

There are other methods, more accurate and correspondingly 
more complicated than this one. The above formula gives the 
surface tension in relation to water. Since water has a tension 
of 73 ergs, per square centimeter, the formula, to read in ergs., 
should be : 

no. of drops of water X density of liquid 
number of drops of liquid 

The surface tension of liquids in dynes per centimeter is 

water 73 

alcohol.- , 22 

ether 16 

Surface tension undoubtedly plays an important role in many 
biological reactions. In phagocytosis or the taking up of bac- 
teria by cells, substances (toxins?) which change the surface 
tension modify the phagocytic power. The clumping of bacteria 
and opsonic index, shows a change in the surface tension of bac- 
teria; similarly anesthesia may in the last anatysis be due to 
changes in surface tension. 



viscosity 345 

The following experiment by Rhumbler (Arch. Entwichlungs- 
mech, 1898 (VII), 249) is interesting in this regard: 

If one tries to pierce a drop of chloroform under water with a 
fine glass rod, it is very difficult or impossible. If now the rod 
be coated with shellac it is sucked into the "chloroform. The 
shellac in this case changes the surface tension in a manner 
similar to the changes that may occur in bacteria by toxins 
or between nervous and muscular tissue by an anesthetic. 

VISCOSITY AND SURFACE TENSION 

The distinctive character of solids is that the relative position 
of the molecules is fixed and can not be changed except by the 
expenditure of a relatively great force. The characteristic of a 
liquid is its tendency to flow. The molecules can be moved with 
relative ease; in gases, the fluidity is much greater than in liquids. 
In liquids, although the particles move relatively easily, the 
fluidity is not perfect. The particles adhere to each other so 
that when a thread of the liquid moves, it drags some of the other 
particles with it, and is in turn held back by them. There is 
thus a movement of the different layers past each other in the 
direction of the flow. This shearing, or internal friction, or 
property of the particles to adhere to each other, is viscosity. 
It is exerted only during movement. Ether, water, oils, balsams 
and waxes are examples of fluids possessing progressively greater 
viscosity. 

The suspensoid colloids, which are solid particles suspended 
in a liquid, have little intimate relation with the liquid in which 
they are suspended, and hence have little viscosity, while the 
emulsoid colloids, which are liquids in liquids, have the properties 
of liquids, and thus a greater viscosity than the suspensoids. 

Surface tension is a surface phenomenon only. It is due to 
the attraction or pull of the molecules on each other; it is exerted 
at all times, but is only manifest at the boundary surfaces of 
liquids, because here the balance of force is upset. The force 
of attraction of the molecules of a fluid for each other is exerted 
at a very short range only — about 6 X 10~ 8 millimetre. All 
molecules in a liquid this distance below the surface will be 
attracted with an equal force in all directions but the layers of 
molecules in the surface fluid will be attracted only by those 



346 



CHEMICAL PHAKMACOLOGY 



below, without a balanced pull from above. Hence they will 
tend to pack together and assume the spherical form, since 
potential energy always tends to become a minimum. The sur- 
face, therefore, contracts as much as the conditions will allow. 
The strength of the pull of the molecules on each other will de- 
pend entirely on the kind or chemistry of the molecule. In the 
case of viscosity, this depends more on the physical state of the 
molecules. 

The tendency of liquids to assume this spherical form can be 
shown : 

1. In Hammerschlag's method of determining the specific 
gravity of the blood; mix benzene and chloroform until it is of the 
same specific gravity as the blood. - Then place a drop of blood 
in the mixture and the blood will assume a spherical form. 

2. Alcohol and water is made to the same density as olive oil. 
Drops of olive oil in this will neither rise nor sink, but will 
assume a globular form. 

3. If conditions are imposed so that the liquid can not assume 
the spherical form, it will assume the smallest surface area that 
conditions will permit, as Van der Mensbrugge's experiment 
shows : " A loop of fine silk is taken and tied to a wire ring. If the 
whole be dipped into soap solution, so as to produce a film, the 
loop floats in the film; the silk thread forming its boundary is 
quite loose, and can be readily moved into any shape by means of 




Fig. 2. — Mensbrugge's Experiment. 



a fine needle wetted with the soap solution. (A) The film inside 
the loop is now broken by touching it with a bit of filter paper cut 



SURFACE TENSION 347 

to a fine point. The loop is immediately drawn to a circular 
form by the tension of the film surrounding it, and can be felt to 
resist attempts to change its shape by the needle. (B) The 
soap solution should be prepared by the method of Boys (1912, 
p. 170), from pure sodium oleate, with the addition of about 25 
per cent, of glycerol." 

Substances that lower the surface tension always collect on the 
surface. Thej^ are never uniformly distributed through the 
liquid; float two small pieces of wood parallel to each other and a 
few millimetres apart. Now let a drop of alcohol fall between 
them. They will suddenly fly apart. The reason for this is that 
the surface tension of alcohol is less than that of water, and the 
drop of alcohol weakens the surface tension film between the 
small pieces of wood so that it breaks and they fly apart. In 
the same way, a film of water on a glass slide breaks when a drop 
of alcohol or ether is added. Camphor placed on water darts 
about over the surface, because it lowers the surface tension 
unequally at different points and the rupture of the surface film 
causes it to move. 

Superficial Viscosity. — This is different from, and independ- 
ent of surface tension, which, as we have said, is a constant stress 
at the boundary of liquids. Surface viscosity is a sort of surface 
friction which is manifest only when there is something to disturb 
or rupture the film. If a liquid assumes a globular form, it is due 
to surface tension, independent of viscosity. Pure water has a 
large surface tension, but no viscosity. It will not foam on 
shaking. A solution of saponin has a marked superficial vis- 
cosity, but no marked surface tension above that of water. A 
magnetic needle placed on the surface of the saponin solution, 
because of the viscosity is not changed in position by the earth's 
magnetic directive force, while it will be changed in a water 
solution. A saponin solution foams on shaking superficial 
viscosity holding the bubble together while the surface tension is 
tending to break it. Oil has a small surface tension but a large 
surface viscosity. 

RELATION OF COMPOSITION TO SURFACE TENSION 

The surface tension of a liquid decreases with the rise of tem- 
perature; hence comparisons should only be made of liquids at 



348 CHEMICAL PHARMACOLOGY 

the same temperature. As might be expected, the surface tension 
varies enormously with composition, but no definite rule can be 
made, nor from chemical composition can predictions of surface 
tension be made with certainty. In a homologous series like the 
paraffin series, increase in CH 2 does not appreciably change sur- 
face tension. Water has a surface tension of 73 dynes, alcohol 
= 22, and ether = 16. Here it would seem that the introduction 
of C 2 H 5 decreases surface tension. Isomeric compounds have the 
same surface tension only when they have similar constitutions. 

Salts increase the surface tension of water, as do gum arabic, 
starch and plum gum. On the other hand, gelatin glue, egg 
albumen, dextrin, cherry gum, and traces of fatty acids, soaps, 
bile acids, tannic acid and resins lower it. 

Since the same chemical substance may be a suspensoid in one 
dispersion medium and an emulsoid in another, we find that the 
same substance may lower surface tension in water and raise it in 
alcohol, and vice versa. Thus the dye, Night Blue, lowers the 
surface tension of water and raises it for alcohol. 

RELATION OF COMPOSITION TO VISCOSITY 

As a rule, viscosity or internal friction increases with molecular 
weight. An iso compound always has a larger coefficient of 
viscosity than the normal compound. In many cases, the mole- 
cular viscosity can be calculated from known viscosity constants. 
Thus the viscositv constant of 



H 


- 44.5 


C 


= 31.0 


hydroxyl 


= 166.0 


carbonyl 


= 198.0 


CI in monochlorides 


= 256.0 


I in monoiodides 


= 374.0 


Double linkage 


= 48.0 


Ring grouping 


= 244.0 



There is a relation between chemical constitution and viscosity, 
although water and alcohol present exceptions to any relation yet 
discovered. In suspensoids the viscosity is little different from the 
water-dispersing medium. There is also little chemical union 
here, it being merely a physical suspension. Colloids, however, 



ADSOKPTION 349 

show a marked viscosity, which depends upon the amount of the 
colloid. One per cent, gelatine increases the viscosity of water 
29 per cent. 

ADSORPTION 

Adsorption is the term applied to surface absorption. This 
process has long been used by chemists to clarify liquids, especi- 
ally for polariscopic work. If a solution contains color, or is 
otherwise opaque, it has been the custom to add powdered char- 
coal, shake, and filter the solution. The coloring material in 
most cases adheres to the surface of the particles of charcoal. 

Filter paper also adsorbs certain colloids. If a piece of filter 
paper is dipped into a solution of Congo red, it soon accumulates 
enough of the dye on the surface so that the solution becomes 
visibly lighter in color. Fuller's earth and kaolin also absorb 
coloring matter and alkaloids in the same way. Bunsen recom- 
mended freshly precipitated ferric hydroxide as an antidote in 
arsenic poisoning. He thought that a compound of basic ferric 
arsenite was formed; 4Fe 2 3 , As 2 3 , 5H 2 0. Recent work shows 
that this is an adsorption compound. 

Charcoal condenses and absorbs gases, and for this reason has 
been used in treatment of gas accumulation in the stomach and 
intestines. The gas is adsorbed. Similarly, palladium and 
platinum adsorbs hydrogen. In the gas chain method of deter- 
mining hydrogen ion concentration, spongy platinum holds so 
much hydrogen that it acts as an hydrogen electrode. 

Selective Adsorption. — Colloidal materials in many cases, for 
unknown reasons, exert a selective adsorption. Sea weeds, for 
example, select iodine from the sea water out of all proportion to 
the amount present. In the same way, plants take up potassium 
as compared with sodium. Adsorption in all these cases may be 
preliminary to chemical combination or chemical action; similar 
to the adsorption of pepsin by fibrin. If a thread of fibrin is 
introduced into a solution of pepsin, most of the ferment is soon 
adsorbed by the fibrin. 

Influence of Salts on Absorption. — Salts seem to have a marked 
influence in some cases. Bone black does not absorb diptheria 
toxin in water, but it is readily absorbed from saline or Ringer's 
solution. Bone black adsorbs sugar in neutral solution, but not 
when acidified with acetic acid. 



350 CHEMICAL PHARMACOLOGY 

The explanation of adsorption is not easy. It is a surface 
phenomenon, and is increased by increase of surface. In colloidal 
solutions, the surface is enormous. It has been calculated that 
in a red colloidal solution of gold containing 0.5 grams of gold in 
a liter, the surface amounts to 8 square meters. Although col- 
loidal solutions of the same sign may adsorb each other as in the 
case of Congo red and filter paper, the kind of electric charge on 
the solid does influence adsorption. When colloids of the same 
sign are adsorbed, it may be that they are amphoteric. 

Acid dyes are in general adsorbed by electro positive colloids 
like clay and colloidal iron, while basic dyes are adsorbed by 
electronegative colloids like kaolin, sulphur, charcoal, silk, cotton, 
etc. 

XXXI. THE REACTION OF LIVING MATTER 

Living matter is alkaline in reaction, but becomes acid after 
death. To determine the reaction during life therefore, it is 
necessary to use an indicator that will act in the living body with- 
out killing it. Such indicators are neutral red and cyanamine, 
the former being an orange red color in alkaline reaction and 
pink in acids. Cyanamine is red in alkaline and blue in acids. 
Acid fuchsin does not stain alkaline protoplasm, but stains it 
red when the protein reacts acid. When the circulation stops, 
protoplasm becomes acid. This may be shown in the following 
experiment: Inject a frog with a solution of acid fuchsin. After 
it has penetrated all the tissues, tie off the circulation of one leg, 
and stimulate the muscles of this leg. On removal of the skin 
from the muscles on the ligated side, it will be found that they 
have become red due to acid formation. It is known that lactic 
acid develops during muscular contraction, in the absence of 
sufficient oxygen. 

In order to determine the reaction of tissues by the use of a 
stain, several conditions must be fulfilled: (1) The stain must 
penetrate the tissue fluids. (2) It must not kill the tissues, 
since the reaction changes after death. (3) Since the tissues 
have oxidation and reduction properties, the stain must not be 
influenced by the oxidation and reduction processes of the body. 

The alkaline reaction of the body is due to excess of OH 
ions. Acid reaction is due to H ions. The concentration of 



REACTION OF LIVING MATTER 351 

these ions present in the body fluids may be determined by a 
number of methods. 

1. The Colorimetric Method. — Solutions of acids of known 
strength in which complete ionization has taken place, or where 
the degree of ionization is known, in terms of a normal solution, 
are colored by some indicators in intensity directly as the con- 
centration of the ions. This being the case, one may determine 
the hydrogen ion concentration of a solution by comparing it, 
when treated with an indicator, with the color solutions produced 
by the same indicator in solutions of known hydrogen ion,, con- 
centration. This is most easily done by using tubes of the same 
bore, and containing the same amount of fluid as the control 
and the same amount of indicator by using a series of tubes of 
known but varying PH concentrations as controls the unknown 
concentration can be found by matching its color with a control 
tube. Such control tubes sealed and with different PH values can 
be obtained, sealed from Hynson Westcott and Co., Baltimore. 

2. Electro Potential Method or Gas Chain Method. — When 
a metal is dipped in a solution of one of its salts an electromotive 
force is set up at the surface of contact. The voltage developed 
depends on the strength of the salt solution. These electrode 
potentials are susceptible of direct measurement, consequently, 
two solutions of different concentration having the same ions in 
common have different electrical potentials. When such 1 solu- 
tions are connected by a conductor, a current flows from the 
stronger toward the weaker. The strength of this current 
depends upon the relative concentration of the two solutions. 
In the case of an acid it is in direct ratio of the hydrogen ions. 
It has been found that a ten fold difference in the ionic concen- 
tration of solutions with common ions is equal to a voltage of 58 
millivolts. Since the logarithm of 10 is 1, the factor obtained by 
dividing the voltage by .058 will give the logarithm of the dilu- 
tion. To determine the hydrogen ion concentration of blood or 
other fluid by this method therefore the difference in the concen- 
tration of a known solution as compared with the concentration 
of H ions in the blood may be represented by the formula; 

e = K log Cone Hi/ Cone. H 2 

Where e = the difference in the potential determined by 



352 CHEMICAL PHAKMACOLOGY 

measurement. K = .058 volts when common logarithms are 

E.M.F. . 

used, consequently — „-„ is equal the number of ten-fold 

dilutions or PH. 

In an actual determination of PH there are many technical 
difficulties to be observed and overcome. While every ten-fold 
dilution makes a difference in potential of 58 millivolts an actual 
determination if made in a chain consisting of — ■ 

H|HC1 n/10|HCl n/100|H would show only 0.019 volts. 
This is due to a contact potential at the junction of the acid 
solutions developed by the difference in speed of H. and CI ions 
and which acts in opposition to the electrode potentials. To 
obviate this error, a neutral conducting solution is placed between 
the acid solutions. Such a solution is KC1. The ions of this 
solution have about the same speed, but in opposite directions, 
consequently neutralize the effect of each other. When such 
a chain is connected we get a voltage of 0.058 -at 20°C. 

H|HC1 n/10|KCl|HCl n/100|H 

Again in actual practice instead of using two hydrogen electrodes, 
as in the above, a standard calomel electrode is used for the known 
solution. The normal calomel electrode has a voltage of 280 
millivolts above the normal hydrogen electrode. Consequently 
the electromotive force E, developed by this when assembled 
with an unknown hydrogen cell (C) would be: 

E = 0.280 - .058 log C or 
E - 0.2 80 ■ 1 .- 

0.058 =-logC = log g = P H . 

If a normal tenth normal calomel electrode be used it has a volt- 
age of .337 above the normal hydrogen electrode, consequently 
0.337 is used instead of 0.280 in the above formula. 

METHOD OF EXPRESSING HYDROGEN ION CONCENTRATION 

The hydrogen ion concentration of body fluids is very close 
to that of water^It would be cumbersome to express frequently 
a dilution of onejmolecule of dissociated H. in ten million litres of 
water by 0.000.000.1. In biologic work we have to deal mainly 
with such dilution's. The adoption of a more convenient method 
of expression is therefore advisable 



HYDROGEN ION CONCENTRATION 353 

Since the ionization constant of water is H times OH = 10 -u 
or H = 10~ 7 and OH = 10~ 7 , and since the factor 10~ 14 is always 
constant, when H increases, OH decreases. 

Thus if H = 10" 1 , OH = lO" 13 , and theoretically if H = 10° 
OH = 10- 14 =1 gram molecule OH in 10.000.000.000,000 litres. 
The older methods of expressing H ion concentration retained the 
constant 10 -7 and until recently the acidity or alkalinity of body 
fluids was expressed: 

2 times 10" 7 

1 times 10" 7 

or 0.5 times 10~ 7 etc. 

Following the suggestion of Sorensen it is customary to express 
the reaction by the reciprocal or cologarithm of the number. 
In reality this is the logarithm of the dilution in terms of normal 
solution. Thus potential of H when H = 10~ 7 is expressed 
PH = 7, and H = lO" 10 , PH *= 10. This method of expression 
is brief but confusing until one gets accustomed to translating the 
numbers, and knowing that the greater the value of PH the lesser 
the acidity, and thinking in terms of logarithms and remembering 
that PHi PH 2 PH 3 etc. differ by powers of 10. 
Thus: Pj< 

PH] = n/10 acid or PH = 1 

PH 2 = n/100 acid PH = 2 

PH 3 = n/1000 acid PH = 3 

PH 6 = n/1,000,000 acid PH = 6 
PH 8 = n/1,000,000 alkali PH = 8 
PHn = n/1000 alkali PH = 11 

PH 12 = n/100 alkali PH = 12 

PH 13 = n/10 alkali PH = 13 

PH 14 = n/1 alkali* PH = 14 

Since the numbers refer to negative logarithms the higher the 
number the fewer H ions in a given volume, while the OH ions 
increase. This is quite comprehensible when we recall that H 
times OH is always 14 or lO" 14 . If PH is 14, it follows that OH 
must be O and if PH 2 is N/10 acid P(OH) x must be N/10 alkali. 
Some confusion may also raise in translating such expressions 
as PH = 2 X 10~ 6 into the more modern figures. One readily 
sees that in terms of normal solution 2 X 10~ 6 is twice as strong 

23 



354 



CHEMICAL PHARMACOLOGY 



as lO" 6 but that PH = 5.70 (Log. 2 
5.70) = n/500.000, is not so obvious. 
Similarity : 



0.3 hence 6-0.3 = 



0.35 X lO" 7 
0.91 X lO" 1 
0.'98 X 10" 3 



n/28.580.000orPH = 7.45 
PH = 1.04 
PH = 3.01 



Since normal metabolism and therefore, normal health, depend 
on the maintenance of the normal alkalinity, pharmacology is 
concerned with the regulating mechanisms and the changes in 
the alkalinity that may be produced by drugs. 



REGULATING MECHANISM 

The blood always contains a mixture of C0 2 , NaHC0 3 , NaH 2 - 
P0 4 and Na 2 HP0 4 . All of these dissociate so weakly and 
normally occur in such quantities that the reaction is constantly 
kept close to PH = 7.2. The normal ratio of NaH 2 P0 4 : Na 2 - 
HP0 4 is stated by Michaelis and Garmendia to be 1 : 5.1 
molecules. If these were the only salts present in a solution of 
water in the proportion of lcc. n/10 NaH 2 P0 4 and 2.5 cc. n/10 
Na 2 HP0 4 we would have a PH of 7.0. The carbonates modify 
this to the PH found in the blood. While the salts which main- 
tain the normal PH are fairly well known the reason why these 
salts are found in the necessary concentrations is not known. It 
should be emphasized that there is a wide margin of safety within 
which they may vary without materially changing the PH. For 
example if m/3 solutions of Na 2 HP0 4 and NaH 2 P0 4 are mixed in 
the following amounts PH = 

Na 2 HP0 4 NaH 2 P0 4 PH = 



1 cc. 


32 cc. 


5.11 


1 


16 


5.42 


1 




6.62 


2 




6.92 


4 




7.22 


8 




7.52 


16 




7.82 


32 




8.12 



BUFFEK VALUE 355 

The lungs and the kidneys play an important part in the regu- 
lation of the H ion concentration, e.g., C0 2 is excreted by the 
lungs. It is continuously formed in digestion. Alkaline salts 
are constantly taken in the foods, especially vegetable foods. 
NH 3 is formed from the digestion of proteins. Acid salts are 
formed and these act as diuretics. Hence, under normal con- 
ditions formation and excretion take place at such pace that the 
body holds a reserve or potential alkalinity. 

It is thus possible to give an account of the mechanism as it 
exists or to state reactions as they probably occur. The basic 
cause, or why, is still beyond the scope of science. 

Under some conditions this mechanism fails and acidosis 
develops. A knowledge of the normal mechanism enables us to 
modify and treat the acidosis. The importance of this may be 
realized since it has been shown by Henderson and Palmer that 
the acid formation in the human organism corresponds to be- 
tween 600 and 700 cc. n/1 acid solution daily. 

ACTUAL AND POTENTIAL ALKALINITY AND BUFFER VALUE 

Sodium bicarbonate reacts slightly alkaline to litmus. This 
alkaline reaction is explained by the fact that in water we have 
H and OH ions. When NaHC0 3 is dissolved in water we also get 
Na, H, OH and C0 3 ions. Consequently there will be a shifting of 

the balance. Since the constant of carbonic acid, — ^ ^^ is 

112^^3 

very small and the constant of ^ ^^ is large, the carbonic 

acid will be suppressed and the constant of NaOH will tend to 
be established. This full constant cannot be reached because 

the NaHC0 3 also has a constant AT TT w ?^ = K and in 

l\ari^u 3 

this case only a certain number of Na + ions can remain in the ionic 

state in the presence of NaHC0 3 . The whole solution, therefore, 

strikes a balance at a strength which reacts slightly alkaline to 

litmus. This balance point is known as the actual alkalinity of 

the solution. This is the PH of the solution as represented by 

the colorimetric or gas chain method. 

If we titrate a solution of sodium bicarbonate with an acid, 

the acid removes the OH ions, but when these are removed, 



356 CHEMICAL PHARMACOLOGY 

others are formed from the bicarbonate which will keep forming 
OH ions in the attempt to form the balance until the whole is 
neutralized by the acid, in the following way. 

NaOH 
Na times OH 
This titratable alkalinity is known as the total or potential 
alkalinity. 

POTENTIAL ALKALINITY OF BLOOD 

The weak alkaline condition of the blood is guaranteed by a 

mixture of H 2 C0 3 , NaHC0 3 , NaH 2 P0 4 . These (buffers) are all 

very weakly dissociating substances and may be considered in 

the blood in a balanced State. 

' H 2 C0 3 ^ , Na H 2 P0 4 T ^ 
= K and ^ T TT ^„ = K 2 



NaHC0 3 N 2 HPO, 

Where K and K 2 are constants, and the sum of these constants 
in terms of H ions is about PH 7.1 to 7.8 

H 2 CQ 3 _ 
NaHC0 3 
If acid be added to this directly or indirectly, as in cases of acido- 
sis, it liberates H 2 C0 3 . This will either break into C0 2 and H 2 0, 
and K kept constant; or it will tend to act with Na 2 C0 3 if such 
be present and restore the constant in that way. If enough acid 
be added or developed, the whole alkali reserve may be exhausted. 
The phosphates are balanced in the same way. According to 
Michaelis and Garmendia, the ratio of 

Na H 2 PQ 4 1 ■ , . , 
Na^H POl = 571 Molecules ' 

Since the normal blood always contains C0 2 , NaHC0 3 and 
Na 2 HP0 4 in this balanced state, the H ion concentration at any 
one time cannot be determined by titration,, because as fast as 
the actual alkalinity is removed, the potential alkalinity is con- 
verted into actual. Consequently, the titration alkalinity is the 
sum of actual and potential. 

This difference between the actual and total alkalinity of the 
blood, is known as the " buffer" value, and NaIIC0 3 and Na 2 - 
HPO4 are the buffers, NaHC0 3 especially. The value of this 
buffer is illustrated by comparing the effect of acid added to a 
liter of water, and to a liter of NaHC0 3 . The reaction of a solu- 



BUFFERS 357 

tion of pure NaHC0 3 is very weakly alkaline. Water is neutral. 
A drop of acid added to a liter of water will definitely acidify it. 
When added to a solution of NaHC0 3 , however, it will not change 
the actual alkalinity, and will not exceed the acidity of C0 2 until 
all of the NaHC0 3 has been decomposed. The amount of acid 
required to do this will depe'nd on the amount of the NaHC0 3 in 
solution, in other words on the buffer value of the solution. The 
carbonates are the chief biologic buffers, and the constant in 
blood plasma of 

™^- - 1/20 

Now PH, or CH as it is sometimes given, is directly proportional 
to this ratio. And any condition in which the ratio of these in 
the plasma is greater than J-^o may be looked On as an acidosis. 
Since CO2 is the principal reagent used by the organism to 
regulate the reaction, it is evident that H ion concentration and 
C0 2 concentration run parallel. Hence knowing the one we can 
calculate the other. Hasselbach (Biochemische Zeitschrift, 1912, 
vol. 46, p. 403) thinks that the hydrogen ion concentration is the 
real stimulus of the respiration rather than CO2. However, 
while many accept the view that C0 2 acts because of the hydrogen 
ion concentration of its solutions, the question of a specific 
action of molecular C0 2 has not been satisfactorily answered. 

ACIDOSIS 

By acidosis is meant the poisoning of the organism with acids, 
due directly to neutralization or depletion of the alkaline reserve 
or potential alkalinity. A better term would be hypoalkalinity. 
Acute poisoning by acids due to corrosion or local action of acids 
does not come under the term acidosis. Most cases are due to 
faulty metabolism, and in such cases oxybutyric acid, diacetic 
acid, lactic acid and acetone are formed and may be found in the 
urine. Acidosis occurs especially in diabetes when as much as 
250 grams of acetone bodies may be produced in a day. The 
normal excretion in adults is from 3 to 15 milligrams per day. 
Until quite recently (1907) diabetes was the only disease in which 
acidosis was known to occur. We now know that it is present 
also in certain nephritic cases, in cholera, in certain intoxications 
in children, starvation, phosphorus poisoning, etc. It often 



358 CHEMICAL PHARMACOLOGY 

happens that these acetone bodies are present in the urine when 
there is no symptoms of acidosis. The presence of acetone 
bodies in the urine develops after the reserve alkalies or buffers 
have been somewhat depleted. This form of acidosis is called 
a ketosis or poisoning by ketone. No special names are given 
to the other acidoses. This depletion may also be caused by the 
introduction of weak acids into the body either by mouth or 
parenterally, and this method of pioducing the symptoms is 
largely responsible for the term acidosis. 

The symptoms of acidosis are mainly those of asphyxia, labored 
respiration, air hunger, cyanosis, coma, and convulsions. Death 
is due to respiratory paralysis. These occur before the blood at- 
tains an acid reaction. It requires three hundred times as much 
acid to render blood acid, as it does to acidify water. This is 
because of the potential alkalinity or buffer value, due to the 
proteins, carbonates and phosphates in the blood which neutralize 
acids. The treatment of acidosis is the administration of sodium 
carbonate, and even in the last stages this is often effective. 

In uremia and diabetes, the acidosis may reach a degree suffi- 
cient to produce coma. Fasting, high fat diet, arsenical and 
phosphorus poisoning, and heavy metals may cause an increase 
in the H ion content of the blood, but not sufficient to produce 
coma. 

Why depletion of the alkaline reserve should cause death while 
the blood is still alkaline is like many other whys — hard to answer. 
We know, however, that certain conditions are necessary for life. 
These are the presence of certain essential chemical elements and 
in addition a balance of these elements. Loeb has shown that 
the ova of fish living in sea water, die in an isotonic solution of 
sodium chloride sooner than they do in distilled water. In this 
case the poisonous action of the sodium can be neutralized by 
traces of calcium. A similar, but perhaps more complex, reaction 
occurs in the human body when the alkaline reserve is depleted, 
i.e., after abnormal loss of the Na + , K + , Mg ++ , and other 
positive ions. When the balance is destroyed other elements 
like potassium, or hydrogen act more as poisons. 

Acidosis is a problem still under investigation and for a clear 
statement of the problem, the student is referred to the little 
book by Sellards, Harvard University Press — 1917. 



acidosis 359 

THE DETERMINATION OF THE EXISTENCE OF ACIDOSIS 

Formerly the presence of acetone bodies in the urine, was the 
only diagnostic test used. This, however, is a relatively late 
sign, and in order to be of much value an earlier indication is 
needed. It was thought, therefore, that in the development of 
acidosis the blood would become less alkaline, and attempts were 
made to titrate the blood with a standard acid. But while this 
method is theoretically sound, it has been found unsatisfactory 
for several reasons: (1) It is hard to remove the coloring matter 
of the blood to allow a satisfactory titration; (2) large volumes 
of blood are required; (3) the proteins of the blood interfere with 
acid titration; and the "buffers" in normal cases vary to a 
greater degree than the possible range of a true acidosis. Acidosis 
is a question of the tissues, hence the blood may not be a true 
indication of the body state as a whole. 

The methods now used to detect acidosis are : 

1. Increased tolerance to sodium bicarbonate. 

2. Urinary changes: 

(a) Increased acidity and acetone bodies. (6) Increase in 
ammonia, (c) Changes in the fixed bases. 

3. Lowered tension of carbon dioxide in the respired air. 

4. Lowered carbon dioxide content of blood = lessened amount 
of carbonate in the blood. 

5. Lowered alkalinity of the blood = increased hydrogen ion 
concentration. 

1. Tolerance to Carbonate. — The normal individual cannot 
take more than 5 grams of sodium bicarbonate a day without the 
urine becoming alkaline. In case of acidosis the sodium bicar- 
bonate is apparently depleted. The tissues absorb and retain 
as much as 100 grams per day before the urine becomes alkaline. 
It has been proven in these cases that the retention is not due 
to defective kidney function. 

2. Urinary Changes. — (a) Increased acidity and acetone 
bodies. Acetone bodies indicate mainly disturbance of carbohy- 
drate metabolism and may have no reference to acidosis. Again 
acidosis may develop in diabetes without the presence of acetone 
bodies in the urine. 

(6) Increase in ammonia. When the fixed bases of the body 



360 CHEMICAL PHARMACOLOGY 

are used to neutralize the acids formed in acidosis there is some 
break-down of protein with the formation of ammonia to aid in 
the neutralization and to make up the alkaline deficit. It was 
therefore thought that the free ammonia excretion in the urine 
would be a measure of the acidosis. . But in primary disturbances 
of protein metabolism the ammonia coefficient may be high, and 
it may be low in acidosis. This may be because ammonia in 
some cases is converted* into stable salts and in other cases urea 
may be decomposed yielding ammonia. 

(c) Change in the fixed bases of the urine, sodium, calcium, 
magnesium and potassium are somewhat used to neutralize the 
acids formed in acidosis. The excretion of these, therefore, in 
the urine may be increased. Since, however, it is the depletion 
of these in the tissues that gives rise .to the symptoms of acidosis, 
their amount in the urine may be lower, at the height of the 
attack. The determination of these bases, therefore, to be of 
value must extend over a number of days. Since the determina- 
tion is tedious and time consuming it is little used. 

3. Lowered Tension of Carbon Dioxide in the Respired Air. 
The normal venous blood carbon dioxide exists under a tension of 
about 6 per cent. (42.6 mms. Hg.) practically 40-50 millimeters. 
An extreme fall of the carbon dioxide is virtually pathognomic 
of acidosis. In four cases of uremia Sellards found 10 to 24 mms. 

The C0 2 content of the alveolar air is practically the same as 
that of the venous blood 37.6 mm.: 42.6 mm. Hg. and more 
closely approaches the content of the arterial blood. For this 
reason, analysis of the respired air has been used to aid in the 
diagnosis. The principle is based on the fact that alkaline 
solutions absorb C0 2 in proportion to the strength of the solution. 
The reaction does not go on to completion and is reversible. 

2 NaHC0 3 *± Na 2 C0 3 + H 2 + C0 2 

or expressed in another form — 

H CO 
x t irnft F a constant (about 1/20). (Isolated plasma only) 
JNariUU3 

Since H 2 C0 3 — >H 2 + C0 2 , and the C0 2 readily penetrates the 
alveolar tissue, a measure of the C0 2 in the alveolar air, is prac- 
tically a measure of the buffer value of the blood. 

4. Carbon Dioxide Capacity of the Plasma (alkali reserve). 
Method of Van Slyke and Cullen — Principle — The plasma from 



PHOSPHORUS 361 

oxalated blood is shaken in a separatory funnel filled with a C0 2 - 
air mixture approximating the composition of the alveolar air 
which has a CO2 tension equivalent to that of arterial blood. In 
this way the sample of blood plasma combines with as much 
CO2 as it is able to hold under normal tension. A measured 
quantity of this saturated plasma is then acidified within a 
special pipette, and its CO2 is liberated by the production of a 
partial vacuum. The liberated CO2 is then measured under 
atmospheric pressure and the volume corresponding to 100 cc. 
of plasma calculated. 

This method is the most useful clinically because of the ease 
with which it can be carried out and because it directly measures 
the alkali reserve of the blood under conditions simulating the 
conditions in the body. 

The H ion concentration of the blood varies so little that it 
is of less value in the diagnosis of acidosis than the measurement 
of the alkali reserve. 1 

XXXII. PHOSPHORUS 

There are two forms of phosphorus, yellow and red or amor- 
phous. The red form is not used in medicine, being inert. The 
yellow is the medicinal variety and it is in the metallic state. It 
appears as a translucent, nearly colorless solid, of a waxy lustre, 
with the consistency of beeswax. 

Phosphorus is very slightly soluble in water, and its solubility 
in alcohol is 1 : 350; it is easily oxidized and burns when exposed to 
the air. On this acount, it should be cut and handled under water. 

In the body it is rather insoluble, and is active only in the finely 
divided metallic state. A large mass may pass through the 
body unchanged, but in the finely-divided state or in solution 
in oil, it is readily absorbed and highly toxic, 0.05 to 0.1 gram has 
proved fatal to man. 

Phosphorus exists in the blood as such and its actions are due 
to the element and not to the oxygen or hydrogen compounds. 
As soon as it is oxidized, it loses its specific action. The chief 
toxic action is to cause fatty degeneration in various organs. 
In therapeutic doses, it is used to stimulate bone formation and 
growth. 

This substance resembles arsenic in many of its reactions. 

For details, see Hawk's Physiological Chemistry, 6 Edition, p. 325. 



362 



CHEMICAL PHABMACOLOGY 



PH 3 , or phosphine, corresponds to AsH 3 , or arsine. PH 3 has 
basic characters like NH 3 and unites with acids to form salts 
of the general formula PH 4 X (phosphonium) . These salts are very 
weak and are decomposed by water into PH 3 and HX. Arsine, 
AsH 3 j and stibine, SbH 3 , do not possess this basic property. 
The H atoms in phosphine can be replaced by alkyl groups to 
form 



P^H or 
>R 


r(-r 
Nee 


or P(-R 


or P^R 
X \ R 


mono 


dialkyl 


tertiary 


quaternary 


alkyl 


phosphine 


alkyl 


phosphoniun 


phosphine 




phosphine 


base 



Only the tertiary phosphine and the quaternary phosphonium 
compounds are formed by the action of alkyl halides RI on PH 3 . 
The mono and di alkyl phosphines are obtained by heating phos- 
phonium iodide, PH 3 I, with an alkyl iodide and zinc oxide. These 
quaternary phosphonium bases, like those of arsenic, antimony, 
etc., exert a strong curare-like action in animals. They are 
strongly basic, and when heated, decompose into a hydrocarbon 
Cn H 2 n + 2 and oxygen compound; 

(C 2 H 5 ) 4 P.OH = C 2 H 6 + (C 2 H 5 ) 3 PO 
An ammonium base under the same conditions would decom- 
pose into an alcohol and trialkyl base : 
/C2H5 



//C2H5 
N^C 2 H 5 



2H5 
OH 



= NR 3 + C 2 H 5 OH 



Oxidizing agents oxidize phosphorus to phosphoric acid. 

In cases of poisoning with phosphorus, the metal will distil 
from an acid solution and can be detected by its phosphorescence 
in a dark room. This phosphorescence is due to the process of 
oxidation of the metal. Oxidizing agents, like potassium perman- 
ganate and hydrogen peroxide in dilute solutions are used as 
antidotes in phosphorus poisoning. 



PHOSPHORUS 363 

Ag forms a compound with P, Ag 3 P. This test is used in 
cases of suspected poisoning with P. A piece of filter paper 
moistened with AgN0 3 , suspended over a solution containing 
P turns black if phosphorus is present, due to the formation 
of silver phosphide Ag 3 P. Other substances like H 2 S in the 
solution will also cause a blackening of the AgN0 3 paper, and 
the test for P is valuable only in proving its absence. Copper 
also forms compounds with P. The formula of the copper 
phosphide is not definite, probably Cu 3 P or Cu 2 P 6 . In cases of 
acute poisoning with phosphorus, the administration of dilute 
copper sulphate 0.5 gram in 100 cc. may be of value in preventing 
the absorption of P. which is still in the gastro-intestinal tract. 
In addition, the copper solution will also act as an emetic. 

The name phosphine may lead to confusion at times, for an 
acridine dye, Philadelphia Yellow, is also known by the same 
name. Acridine, Ci 3 H 9 N, is prepared from ortho-amino-diphe- 
nyl-methane; 

X NH 2 X CH X 

o. amino diphenyl acridine 

methane 

Phosphine, or Philadelphia Yellow, is a beautiful yellow dye 
which forms red colored salts, and is a mixture of the hydro- 
chlorides of asymetrical diamido-m-tolyl acridine. It is obtained 
as a by product in the manufacture of rosaniline. Its formula is; 



NH 2 .C 6 H 4 




Phosphine 



364 CHEMICAL PHARMACOLOGY 

It is a protoplasm poison, especially for protozoa, but has been 
used without success in malaria. 

The Fate of Phosphorus in the Body 

The fate in the body is obscure. It is highly probable that 
it is oxidized to some extent in the body. It is hard to tell this 
from direct chemical examination because the phosphates vary 
normally, more than a toxic dose of phosphorus could change the 
phosphate content of the urine. Some may be excreted by the 
lungs; but the statement that the breath may become phosphores- 
cent is not given much weight : Unknown organic combinations of 
phosphorus have been found in the urine. 

ARSENIC COMPOUNDS 

Metallic arsenic is non-toxic, while its compounds are all 
toxic. White arsenic, As 2 3 , which is an anhydride of arse 
nious acid, As 2 3 + 3H 2 = 2H 3 As0 3 , is the most important 
compound. Arsenious acid, however, cannot be isolated 
since on evaporation of its solution arsenic trioxide is again 
obtained. This is also known as white arsenic. A 1 per 
cent, solution of this in 2 per cent, potassium bicarbonate 
solution is known as Fowler's solution, and is a favorite prepara- 
tion in medicine. Asl 3 , arsenious iodide, is also used in medicine 
in the form of liquor arseni et hydrargyri iodidi. This is a 
1 per cent, solution each of Asl 3 and red mercuric iodide Hgl 2 
in water. Sodium arsenate, Na 2 H.As0 4 .7H 2 is used to some 
extent. 

Atoxyl, sodium arsinalate, or sodium p amino-phenyl arsenate 
is a compound formed when anilin and arsenic acid are heated 
together 

/OH 
C 6 H 5 NH 2 + As(OH) 3 = C 6 H 5 NH 2 - O - As-0 

\OH 
p. amino-phenyl arsenate 
/OH 
NH 2 C 6 H 4 - As = + H 2 
\OH 

p. amino-phenyl arsenic acid 



ARSENIC 365 

The sodium salt of this is atoxyl. The Na replaces an hydroxyl H. 

/OH 
Acetyl atoxyl CH3.CO.NH.CeH4. — As =0 is also employed. 

\0H 
Arsacetin is the sodium salt of this, or 

/OH 
CH 3 CO.NH.C 6 H 4 - As^O 

\ONa 

7 0H 
A OH 
//OH 

\ 



Arsenic acid has the formula H 3 As0 4 or As' 





When two of the OH. groups are replaced by methyl groups, we 
have cacodylic acid: — 

/CH 3 
As— CH 3 
^OH 
X 
Cacodylic acid is formed when potassium acetate is distilled with 
arsenious acid: — 

As 2 3 + 4CH 3 COOK -> (CH 3 ) 2 = As - O - As = (CB 3 ) 2 

+ 2K 2 C0 3 + 2C0 2 
cacodyl oxide 
Cacodylicoxide when treated with HC1 yields cacodyl chloride: 
(CH 3 ) 2 = As - O - As = (CH 3 ) 2 + HC1 = 2(CH 3 ) 2 As - CI. 
On oxidation this yields cacodylic acid : 

/CH 3 /CH 3 

As— CH 3 + 2H 2 + 20 -> 2 As— GH 3 
\C1 || \0H 


/CI 
As— CH 3 
\CH 3 
Sodium cacodylate is the most important salt of cacodylic acid. 

/CH 3 

= As— CH 3 

X)Na 



366 CHEMICAL PHARMACOLOGY 

If the three hydroxyl hydrogens of arsenic acid are replaced by 
Na, sodium arsenate is the product. This, acted upon by 
methyl iodide in alkaline solution, yields sodium methyl arsenate 
or arrenhal. 



/ 



ONa /CH 



= As— ONa + CH 3 1 = = As— ONa 
\ONa \ONa 

Sodium arsenate arrenhal 

Arsphenamine or salvarsan "606" dioxy diamino arseno benzol 
The number "606" refers to the laboratory research number. 
This substance is a derivative of arseno benzene, 

C 6 H 5 - As = As - C 6 H 5 , 

which is analogous to azo benzene, 

C 6 H 5 - N = N- C 6 H 5 . 

The following reactions illustrate its preparation: 

(I) When phenol and arsenic acid are heated together a conden- 
sation takes place in the para position: 

/OH 



HO< 



HHO; - As^O = 

\eo 



.OH 
As==0 + H 2 
\)H 

p. phenol arsenic acid 

When this is treated with nitric acid, a nitro derivative is formed : 

,OH 

• 0+ HONO2 = 
OH 

N0 2 

.OH 

As + H 2 
^OH 



ARSPHENAMINE 367 

On complete reduction, this yields a condensation product : 

N0 2 

/OH 
y As = O + 2 OH -> 

\OH 

As - — 




NH< 



NH< 



OH salvarsan OH 

Arsphenamine or salvarsan is a light yellow crystalline powder 
and yields a solution in water with an acid reaction. When given 
intravenously, the solution should be well diluted and slightly 
alkaline. 

Neo-arsphenamine or neo-salvarsan, (914) is a soluble prepa- 
ration of salvarsan. Jt is sodium di-amino dihydroxy arseno- 
benzene methanal sulphoxylate ; 



As= 



=As 



NH 2 




NH(CH 2 0) OSNa 



OH 



It is prepared by precipitating a salt of arsphenamine with 
sodium methanal sulphoxylate and dissolving the precipitate 
in alkalies. It is an orange yellow powder of peculiar odor and 
is unstable in the air. 

Fate of Arsenic in the Body 

Arsenic is absorbed rapidly and excretion by the urine begins 
in about seven hours and lasts several days, though it may con- 



368 CHEMICAL PHARMACOLOGY 

tinue for' three months. Tt is excreted mainly through the kid- 
neys. Since it irritates the kidneys the amount of urine in toxic 
cases is greatly diminished. 

Regarding the retention of arsenic by the various organs, the 
liver retains the most, but the kidneys, spleen and muscles all 
may contain arsenic. Only traces are found in the brain. It has 
been detected in the cancellous bones of the skull and vertebra? 
after it has disappeared from all the other organs. The poison 
is probably combined in the organs as arseno-nucleins. Since 
the nucleins are the most active seats of life it probably kills by 
an action here. 

Binz and Schultz thought that the action of arsenic was due 
to an alternate reduction and oxidation of it in the tissues. 
Arsenious acid being oxidized to arsenic acid and the reverse 
reaction occurring also. In this way oxygen is alternately 
withdrawn from and supplied to the protoplasm. If such a 
process takes place it must be very gradual otherwise we cannot 
explain why arsenious acid is so much more powerful than arsenic 
acid. 

Gautier thought arsenic to be a normal constituent of the 
thyroid gland, but there seems to be no basis for this, and what 
Gautier found must have been taken as medicine or otherwise. 

For a complete report on the Chemistry of the Organic Com- 
pounds of Arsenic and Antimony — see Organic Compounds of 
Arsenic and Antimony by Gilbert T. Morgan, Longmans Green 
and Co. 1918. 

XXX11I. HEAVY METALS 

We include under the term heavy metals, antimony, mercury, 
iron, lead, copper, zinc, silver, bismuth, aluminum, gold, plat- 
inum, manganese, cadmium, nickel, cobalt, tin, thallium, van- 
adium, tungsten, uranium, etc. Of these, only the first twelve 
are of importance in medicine, the others being of toxicologic 
interest only. Phosphorus and arsenic are important, but they 
are not usually classified with heavy metals. 

The metals themselves are inactive, and it is only in the form 
of soluble salts that they exert any action. It must be remem- 
bered, however, that the solubility in albumen may be different 
from that in water, although usually only those salts that are 
soluble in water are active. 



HEAVY METALS , 369 

Heavy metals have two actions: (1) local, and (2) general, 
or the action after absorption. 

The salts of the heavy metals form combinations with proteins, 
and local action is due to this combination. According to the 
reactivity, strength, and extent of the combination, the salts of 
the heavy metals may be astringent, irritant, styptic, caustic or 
corrosive. Since the same salt in different concentrations may 
exhibit all these actions, it is impossible to classify metals under 
these heads. From a practical standpoint, however, they may 
be classified as follows : 

1. Styptics — ferric chloride, dried alum. 

2. Astringents — alum, lead acetate, basic lead acetate, zinc 
oxide, bismuth subnitrate, ammoniated mercury. 

3. Astringent and corrosive — iron salts, zinc sulphate, zinc 
acetate, copper acetate, silver nitrate, lead nitrate, lead iodide. 

4. Corrosive — mercury salts, zinc chloride, tin chloride, anti- 
mony chloride, copper sulphate. 

As a rule, the greater the ionization, the greater the action. 

The salt formed by the union of a metal with protein is a pro- 
teinate, e.g., argenti proteinas or protargol. .It is not of constant 
composition, but varies with the kind of protein and the amounts 
of the protein and metal used. Thus the salts are not true chem- 
ical compounds. The precipitate when formed may redissolve, 
or go again into solution if too much of the reagent or of the 
protein solution is added. This is especially true in the case of 
lead salts, and is readily understood in the light of the phenome- 
non of precipitation. 

Explanation of Precipitation 

Proteins are, emulsoid colloids. Colloids remain in solution 
because they are electrically charged, either negatively or posi- 
tively. Proteins belong to the class of colloids, which are usu- 
ally negative, and remain in solution as long as they retain this 
charge. Because the charge is the same throughout, and as like 
charges repel each other, the protein remains in solution but 
when the charge is neutralized, precipitation occurs. According 
to the cause, precipitation may be due to: 

1. Spontaneous precipitation. 

2. Gelatinization. 

24 



370 CHEMICAL PHARMACOLOGY 

3. Coagulation by enzymes and heat. 

4. The addition of electrolytes. 

5. Other colloids of opposite sign. 

Examples of these changes in drug chemistry are : 

1. The spontaneous decomposition of a solution of silicic acid 
or water glass. 

2. The precipitation of gelatin or agar due to loss of water by 
evaporation. Their solution may be considered as hydrophylic 
compounds. Evaporation necessitates an internal rearrange- 
ment and a loss or neutralization of the charge. These charges 
are reversible, an addition of water again causing the formation 
of a colloidal solution. 

3. Heat coagulation, and the changes caused by enzymes are 
well known in the coagulation of white of egg, and the souring 
of milk. These coagulations are irreversible. 

4. The precipitates formed by electrolytes are divided into 
two groups (reversible and irreversible), depending on the na- 
ture of the precipitate or coagulate. 

Salts of Ba.Sr. and the heavy metals form precipitates which 
are irreversible. 

The difference between reversible and irreversible precipitates 
is due to a fundamental change and molecular rearrangement in 
the case of the irreversible ; while in the reversible there is merely 
a neutralization of the electrical charge. Accordingly, proteins 
may be precipitated in three forms: 

1. Unaltered, i.e., by salting out or neutralization of the 
charge — reversible. 

2. As albuminates, by coagulation \ . ., , 

3. Insoluble salts of metals / 

Both ions of a salt are important in precipitation. Which of 
the two is more important depends on the nature of the colloid 
to be precipitated. For example: colloidal iron is a positive 
colloid, and is much used to remove proteins from the blood. 
The positive charge on the iron salt is neutralized by the negative 
charge on the protein and both are precipitated. Colloidal iron 
is also precipitated by a solution of MgS0 4 , or Na 2 S0 4 or almost 
any salt. In this case it is the negative ion or anion which acts 
to neutralize the positive charge of the iron. 

In the precipitation of proteins, however, the same explanation 



COLLOIDS 371 

holds; but since the proteins are negatively charged it is the posi- 
tively charged ion or cathion that is more important as a protein 
precipitant. Since the precipitation is due to a neutralization, it 
follows that if the colloid is negative the precipitating ion is always 
the cathion, if positive, the anion. 

Bivalent ions are more active in causing precipitation than 
monovalent, and polyvalent more powerful than bivalent. The 
valence of the ion of the same sign as the colloid has no influence 
on the action. 

Aside from the neutralization, there are, of course, especially 
with the heavy metals, proteinates formed that can not be 
explained on this simple basis. These salts, while not so definite 
as the heavy metal combinations with sulphates, carbonates, etc. 
are of the same nature. 

The action of heavy metals when taken internally is due to the 
chemical local action of the metal on the stomach and intestine. 
The nature of the acid in the salt is of importance, as is also the 
nature of the precipitate, slimy or granular. 

Nitrates are more irritant than acetates because the nitric acid 
liberated in the reaction is a more powerful irritant than acetic 
acid. 

When the precipitate is granular, the acid liberated penetrates 
to the tissue below more readily than when the precipitate is 
slimy in nature. Corrosive sublimate, for these reasons, pene- 
tiates deeper and is more corrosive than lead acetate. 

Local reactions of the heavy metals when taken internally are; 
loss of appetite, pain and discomfort, nausea, vomiting, purging, 
congestion, hemorrhages. These are all the result of the irritant 
and corrosive action of the metal. Ulcers may result after a 
time due to bacterial action on the dead tissue. 

The action after absorption is also the result of a combination 
of the metal with the protein. 

There is little difference in the action of the metals after ab- 
sorption. Iron is just as toxic as arsenic when it is introduced 
into the blood, but it is not absorbed rapidly from the stomach; 
consequently it is not ordinarily toxic. 

The toxic action of the heavy metals on the central nervous 
system is manifested by delirium, hallucinations, mania, stupor, 
and coma. Convulsions indicate that the motor areas, basal 



372 CHEMICAL PHAEMACOLOGY 

ganglia and spinal cord are affected. Peripheral neuritis occurs 
especially with lead and antimony, not differing from the neuri- 
tis caused by alcohol, arsenic or toxins. 

The astringent action of the heavy metals is due to several 
factors : 

1. The metal and protein unite to form an albuminate, and the 
resultant liberated acid has an astringent effect. 

2. The metal may be absorbed locally and exert a constricting 
action on the local vessels. 

3. Insoluble salts like cerium and bismuth cover and protect 
the surface mechanically. 

Absorption of heavy metals is slow, with the exception of salts 
of mercury. Mercury is the only volatile metal and volatility 
aids absorption. Whether the volatile character of the free 
metal conveys any properties on the ion in the salt is not known. 

The matter of excretion of heavy metals may be described as 
follows; the body stores up the metals in the liver, spleen and 
other organs, slowly eliminating it from them. This is done by 
the kidneys and intestine, thus showing the reason that nephritis 
is a prominent symptom. Heavy metals are also excreted into 
the gut, and have a specific action on the gastro-intestinal tract. 
This effect is more marked with arsenic, phosphorus and anti- 
mony than with the heavy metals. By whatever course they 
enter the body, there is always an inflammation of the gastro-in- 
testinal tract throughout its extent, as much of the metal leaves 
the body by this route. 

COLLOIDAL METALS 

The colloidal metals especially used in medicine are gold, cop- 
per, platinum and silver. These are simply finely divided metals 
having an electrical charge, which is positive. They are suspen- 
soid colloids. 

The methods for preparing colloidal metals are: 

1. The disintegration of heavy metals by means of an electric 
current strong enough to cause sparks under water. The metal 
is used as electrodes. 

2. Reduction of dilute solutions of the salts of the metals by 
various reducing agents. They are prepared in water free from 
electrolytes as they can not be kept for any time in the presence of 
salts. 



INORGANIC ACIDS 373 

The method of preparation by an electric current, and the effect 
of electrotytes in causing precipitation, together sustain the 
opinion that colloids bear electric charges. This properly differ- 
entiates true suspensions from suspensoid colloids. True suspen- 
sions will settle out on standing at rest, while suspensoid colloids 
are little influenced by gravity and remain suspended. 

The basis for the use of colloidal metals in medicine is that 
traces of copper and other heavy metals in water in a vessel of 
one of these metals, contain none of the metal detectable by 
chemical means, yet they prevent the growth of, and sometimes 
kill, unicellular organisms. When the metallic surface is in- 
creased as in the colloidal solutions, a greater chance is given for 
this action, and the colloidal solutions can be injected into tumors 
or applied to mucous surfaces. The value of colloidal metal 
solutions is still problematical, for while solutions such as argenti 
proteinas unquestionably is efficient in some infections of the 
eye, it is probably less efficient than a 1 per cent, solution of 
silver nitrate. 

XXXIV. INORGANIC ACIDS 

The inorganic acids of importance in pharmacology are boric, 
hydrochloric, sulphuric, nitric and phosphoric. Chromic and 
hydroflouric acid are of small importance. 

The acids when used as such owe their action to the hydrogen 
ion, and are protoplasm poisons. Protoplasm, which is essen- 
tially alkaline in reaction, cannot contain life if this alkalinity is 
neutralized by acids. If strong acids come in contact with pro- 
toplasm, they may disintegrate it, hence they are corrosive poi- 
sons. For this reason, strong acids, when applied to the skin, 
destroy the epidermis. Acids, because of this corrosive action, 
are sometimes used to destroy warts. The corrosive action is 
more marked when the acids are applied to mucous membranes ; 
even a small quantity of a strong acid in the eye may destroy the 
sight. The mucus membrane of the mouth, esophagus and stom- 
ach may be destroyed if such acids are swallowed. In dilute 
solutions, they are absorbed rapidly, and are neutralized, and 
exist in the blood in the form of salts. 

The process of neutralization differs in different animals. 
Herbivora, because of their food, have a greater reserve of fixed 



374 CHEMICAL PHARMACOLOGY 

alkalies, mainly sodium and potassium, which are first used to 
neutralize any acid that may be taken. When these alkalies are 
used below a certain level, proteins are broken down and ammonia 
is formed to neutralize the acids. Carnivorous animals, on 
the other hand, are accustomed to the development of acids 
from their protein food, and as their food contains a limited quan- 
tity of fixed alkali, the normal process of neutralization is the 
formation of ammonia. Hence carnivorous animals, because 
they can more readily form ammonia are in a better position to 
protect themselves from the neutralizing influence of acids. 
Herbivorous animals consume large quantities of organic salts 
of the alkalies in their food, and have a greater immediate reserve 
of these salts than carnivorous animals, but the mechanism to 
form ammonia quickly is lacking, which is always at work in the 
carnivora, and, in case of poisoning, requires only a little speeding- 
up. Herbivora, then, are more easily poisoned with acids than 
carnivora. The absorption of dilute acids in dogs does not mater- 
ially change the available alkali of the blood, while in rabbits, 
the same amount of dilute acid causes a reduction of from twenty 
five volumes to two volumes per cent, in the carbonic acid in the 
blood. When this occurs, respiration becomes deep, labored 
and rapid, afterwards, weak and shallow, and finally ceases. 
The heart continues to beat after respiration has ceased. 

The acids are excreted by the kidney in the form of salts. If 
any considerable quantity has been taken, the body conserves its 
alkali reserve and the salts are excreted as acid salts. 

To counteract the effect of acids, alkalies are used : Since most 
alkalies themselves are corrosive, one must exercise care in their 
use. The most available is sodium bicarbonate or baking soda. 
This may be used without much danger. Lime water can also 
be used, but its neutralizing power is little since calcium oxide 
is soluble only in about 800 parts of water, If sodium carbonate, 
or sodium hydroxide be used, very dilute solutions can be used 
without injury, but if stronger solutions are used they exert a 
caustic action perhaps more harmful than the acids. 

XXXV. SALT ACTION 

By salt action in pharmacology, we understand those actions 
which are not specific but which may be elicited by any salt, 



SALT ACTION 375 

and are due fundamentally to processes of osmosis, diffusion, and 
dialysis. The effects of sodium chloride on red blood corpuscles 
are an example of salt action. If the salt is iso-tonic, no action 
takes place, while if it is hyper tonic, crenation occurs. If the 
salt is hypotonic, the cell will absorb water and a swelling or 
edematous condition results. If the salt is applied to the nerve 
in hypertonic solutions, it will cause a twitching of the muscle 
through its action on withdrawing water from the nerve. 

Ion action differs from salt action in that the action is specific. 

+ 
Thus, KCN is a pronounced poison because it ionizes into K and 

CN. The CN is a violent poison. The same amount of CN 
in potassium ferro cyanide which does not ionize but remains as a 
salt is without action. 

Diffusion. — When two or more gases are brought together with 
no physical barrier to separate them, they soon form a homogene- 
eous mixture; e.g., when gas is liberated in a room, it soon spreads 
throughout the whole space and mixes uniformly with the oxygen 
and nitrogen of the air. This process of mixing is called diffusion. 

Osmosis.— If two miscible liquids are placed in the same vessel, 
in a short time they will diffuse or mix uniformly just as gases. 
This process is due to the movement of the molecules and is slower 
in liquids than in gases. If the liquids are separated by a mem- 
brane and the diffusion occurs through the membrane, the proc- 
ess is known as osmosis. Not only water but salts and crystal- 
loids generally will pass through the membrane. Colloids diffuse 
through a membrane very slowly. 

If the process of osmosis is used to separate one substance from 
another, as in the separation of crystalline substances from 
colloids, the process is known as dialysis. 

GAS PRESSURE IN RELATION TO OSMOTIC PRESSURE 

It has been proved that the osmotic pressure, or osmotic 
suction, of a crystalloid is the same as would be exerted by the 
same number of particles of a gas if it were confined in the same 
space. To illustrate; if a gram molecular weight of any gas 
oxygen H 2 = 2 grams 2 = 32 grams N 2 = 28 grams is confined 
in a liter volume at 0° (zero) centigrade, it will exert a pressure 
of 22.32 atmospheres, or the converse of this a gram molecular 



376 CHEMICAL PHARMACOLOGY 

weight of any gas at ordinary pressures occupies a volume of 
22.32 litres. This is in accordance with the gas law; Pressure 
times volume = pressure times Volume, or Pv = pV. 

Crystalline substances do not pass into the gaseous state 
without decomposition, but when in solution they exert the same 
pressure as they would if they were in a gaseous state in the same 
volume. For instance, the gram molecular weight of cane sugar, 
C12H22O]], is 342 grams. If this amount of cane sugar is dis- 
solved in water and made up to 1 litre, it will exert a pressure of 
22.32 atmospheres. An ion exerts the same influence as a 
molecule, consequently, if a substance which contains two ions in 
the molecule is completely ionized, the pressure will be doubled, 

as in a very dilute solution of sodium chloride. In the case of 

+ + — 

sodium sulfate, which ionizes into Na — Na — S0 4 , complete 

ionization would make the pressure three times the molecular 

pressure. In sodium phosphate, Na 2 H P0 4 , in complete ioniza- 

+ + + 

tion Na — Na — H — P0 4 the complete pressure would be four 

times the molecular. Calculation of osmotic pressure of solutions 
that do not ionize is an easy task. All that is necessary is 
to know the molecular weight of the substance and the concentra- 
tion. For example: 

I. To calculate the osmotic pressure of 5 per cent, cane sugar 

solution. 342 grams in 1 liter or 34.2 per cent. — 22.32 atmos- 

5 
pheres. 5 per cent. = wt^ times 22.32 atmospheres. 

II. 5 per cent, solution of NaCl — assuming no ionization — 

58.5 grams in 1 liter or 5.85 per cent. = 22.32 atmospheres 

5 
5 per cent. == ^-^ times 22.32 atmospheres. 

O.oO 

If there is a certain percentage of ionization however the osmotic 
pressure will be increased accordingly. 

DIFFICULTIES IN DETERMINING OSMOTIC PRESSURE 

The pressure exerted by a molecular solution is so enormous 
that it is hard to get a semi-permeable membrane that will stand 
the strain. Before the theoretic level is"reached, most mem- 
branes rupture. The nearest approach to a semi-permeable 



SALT ACTION 377 

membrane that would stand the strain was devised by Pfeffer. 
He used a porous clay cell and filled it with a solution of copper 
sulfate and set it in a solution of potassium ferro cyanide. As 
the two solutions permeated the porous clay they met and formed 
a precipitate of copper ferro cyanide, which functions as a semi- 
permeable membrane. Most animal membranes and collodion 
tubes are only partially semi-permeable. Salts will pass in both 
directions and while they answer for the ordinary purposes of 
dialysis they cannot be used to determine or measure the extent of 
osmotic pressure. In biological work the osmotic pressure is 
not determined directly, but indirectly, from the freezing point. 

RELATION OF OSMOTIC PRESSURE TO THE BOILING POINT AND 
FREEZING POINT OF SOLUTIONS 

The rise in the boiling point of a water solution of a substance, 
provided the substance does not change on heating, bears a 
direct relation to the number of molecules or ions in the solution. 
An ion exerts the same influence as a molecule. Since most 
biological fluids contain proteins, and change in physical proper- 
ties on heating, the boiling point method cannot be used. 

Freezing Point Method.— This method is available in biological 
work. It is simple and convenient. Each mol-ion added to a 
liter of water depresses the freezing point 1.85°C. This depres- 
sion of the freezing point is designated by A. Solutions with the 
same freezing point have the same osmotic pressure. To calculate 
the freezing point of a pure substance in water, we must know its 
formula and the per cent, of the solution. For example; to calcu- 
late the freezing point of 1 per cent. NaCl. A molecular solution 
of sodium chloride is 58.5 grams to the liter, or 5.85 per cent. 
This depresses the freezing point 1.85°C. 1 per cent, solution 

depresses it -^ r of 1.85° C. or. 316°C. This assumes no ioniza- 
tion. In actual work it is found that A = 0.589 which shows a 
high per cent, of ionization. The freezing point of a 1 per cent, 
solution of cane sugar, since a molecular solution of sugar — 342 
grams in the liter or 34.2 per cent, is ^ 4 . 2 of 1.86°C. or -0.054°C. 
To Calculate the Osmotic Pressure from the Freezing Point. 
The osmotic pressure of a molecular solution is 22.32 atmospheres 
or 16,986 millimeters of mercury. This height of mercury is 



378 CHEMICAL PHARMACOLOGY 

equivalent to a temperature reduction of 1.86°C. The osmotic 
pressure of 1 per cent, cane sugar is therefore 16,986 : 1.86 : .054 : 

0.054 
X.or ' fi times 16,986 = 493 millimetres of mercury. 

SALTS IN THE BODY 

Certain salts are necessary for life, but the amount of these is 
small (see p. 2) . They exist in the body mainly as ions. The 
freezing point of mammalian blood is .526; (varies from .480 to 

.605); hence the osmotic pressure is j-^-z times 22.3 atmosphere 

or about 7.25 atmospheres. This is due almost entirely to 
salts, sugar and urea. The proteins contribute but a small part 
to the total osmotic pressure. 

The average freezing point of serum is -0.6°C. 0.95 per cent. 
NaCl has this same freezing point and is, therefore, iso-osmotic 

or isotonic. The osmotic pressure calculated from this is t^X 

22.32 = 7.24 atmospheres. 

Calculated on the percentage basis and assuming no ionization, 
a molecular solution of NaCl = 58.5 grams in a litre or 5.85 
per cent. = 22.32 atmospheres. .95 per cent. NaCl should equal 

95 
-^rz of 22.32 atmospheres = 3.62 atmospheres. Assuming no 

ionization, the osmotic pressure here is just one half of that found 
by direct determination, hence normal saline must be completely 
ionized. 

The action of sodium chloride when injected into the circulation 
is not noticeable on the blood pressure or circulation. A solution 
of KC1 of the same osmotic pressure causes a pronounced depres- 
sion of the heart. Since CI, as judged from the action of NaCl, 
has no action, the action obtained from KC1 must be due to the 
K ion. This illustrates the difference between salt action and 
ion action. Isotonic saline solutions can exert no salt action, 
and if an action results, it must be an ion action. Both ions 
usually have some action, but in most salts one of the ions is 
much more powerful pharmacologically than the other. K in 
the KC1 is the important ion, but in the case of KCN the CN 
ion is so much more toxic than the K that the action of KCN is 



TOXICOLOGY 379 

attributed almost entirely to the CN ion. Some drugs are not at 
all dissociated in the body and therefore the only action they 
exert is the molecular or salt action. Ether, sugar and alcohol are 
not ionized. They exert only a salt action. Some of these, 
however, may be broken down in the body and their cleavage 
products may form ionizable compounds. Alcohol and sugar 
3'ield C0 2 . This may react with the fixed bases of the body to 
form carbonates, Na 2 C0 3 , etc. The carbonates may be hydro- 
lyzed to form NaOH which ionizes into Na + OH. While 
alcohol contains the group OH, it does not ionize and it exerts 
only a molecular action unless broken down. 

SALT ACTION IN PHARMACOLOGY 

Salts have the same importance in pharmacology as in physiol- 
ogy, but in addition, many salts used as drugs owe most of their 
action to osmosis, dialysis, and diffusion. This is especially 
true of the cathartic salts. Because these are not absorbed from 
the gut, the physical properties above enumerated suffice to 
explain their action. In most cases when salt is administered 
some is absorbed, and may either be excreted into the gut again 
or by the kidneys. When excreted by the kidneys, salts exert 
osmotic effects on the convoluted tubules. Some are reabsorbed 
from the tubules, others such as sodium sulphate, are but little 
reabsorbed and hence act as better diuretics than the chloride. 
The diuretic action of these salts can be seen best when they are 
injected into the circulation. Other instances of the osmotic 
effects of salt might be cited, but none more impressive. 

XXXVI. TOXICOLOGY 
THE ISOLATION OF POISONS 

For analytical purposes, poisons may be divided into groups 
as follows : 

Group I. — -Volatile poisons which distil with steam from acid 
solution without decomposition, and can be detected in the 
distillate. They are arranged in the order of their boiling point — 
which is about the order in which they would appear in the 
distillate : 



380 



CHEMICAL PHAKMACOLOGY 



Chloral hydrate 97° 

Iodoform — m.p 119° 

Benzaldehyde 179° 

Phenol 180° 

Aniline 183° 

Creosote 200°+ 

Nitrobenzene 208° 



Yellow phosphorus 

Hydrocyanic acid 26° 

Carbon disulphide 46° 

Acetone 57° 

Chloroform 61° 

Methyl alcohol 67. 4 C 

Ethyl alcohol 78° 

Group II. — Non-volatile organic substances which can be ex- 
tracted from extraneous matter with hot alcohol, after acidifica- 
tion with tartaric acid. The principal members of this group 
are: 

The alkaloids, neutral principles, some glucosides and bitters, 
synthetic organic drugs such as the sulphone hypnotics, the 
antipyretics, phenacetine, acetanilide, antipyrine, pyramidone, 
etc. After separating protein, fats, gums, resins, etc. that may 
be mixed with these drugs in cases of poisoning, non-volatile 
poisons may be subdivided into groups based on analytical 
methods. One of the methods is the Stas-Otto process which 
consists in extracting the liquid in a separatory funnel with 
immiscible solvents. Those extracted with ether when the 
solution is acid are: 



A. Acetanilide 
Antipyrine 
Caffeine 



Colchicine 
Picric acid 
Phenacetin 



Picrotoxin 
Salicylic acid 
Veronal 



B. Those extracted with ether when the solution is made 
alkaline with sodium hydroxide : 

Aniline Codeine Pilocarpine 

Antipyrine Coniine Pyramidone 

Atropine Hydrastine Quinine 

Brucipie Narcotine Scopolamine 

Caffeine Nicotine Strychnine 

Cocaine Physostigmine Veratrine 

C. Those extracted with ether, in a solution made alkaline with 
ammonia. The solution from the sodium hydroxide extract, is 
firs! made slightly acid, and then alkaline with ammonia. Ether 
will extract from this alkaline solution apomorphine and traces 
of morphine. 



TOXICOLOGY 381 

D. Those extracted by chloroform. After the ether extract 
from the ammoniacal solution has been removed, chloroform 
will extract the following, if present : 

Antipyrine 
Caffeine 
Morphine 
Narceine 

Group III. Metallic Poisons. — These may be found in the 
residue after the extraction of the organic poisons, or an original 
portion may be used to test for them. Before testing for these, 
all organic matter must be destroyed. The most important 
metallic poisons are: 

Antimony Cadmium 

Arsenic Chromium 

Barium Lead 

Bismuth Mercury 
Tin 

Group IV. — Poisons not in groups and for which special direct 
tests must be made — the most important are : 
(a) The mineral acids— HN0 3 , HC1, H 2 S0 4 . - 
(6) Oxalic acid. 

(c) Alkalies— NH4OH, NaOH, KOH. 
{d) Chlorates. 
(e) Miscellaneous organic: 



Cantharidin 


Opium 


Cytisine 


Santonin 


Digitalis — glucosides 


Saponins 




Solanin 


Ergot principles 


Sulphonal 


Pilocarpine 


Trional 


Ptomaines 


Toxalbumins- 




Abrin 




Crotin 




Curcin 




Ricin 




Robin 



382 CHEMICAL PHARMACOLOGY 

METHODS OF ISOLATING POISONS 

The tests made with pure substances, give one but little 
conception of toxicology. The isolation of poisons, from stomach 
contents or from the liver, and the preparation of these for 
testing is more important than the tests, and much more difficult. 

THE ISOLATION OF VOLATILE POISONS 

The volatile poisons include those that are volatile in steam in 
acid solution. The acid used must be non-volatile, especially 
suitable is tartaric, but dilute sulphuric or phosphoric may be 
used. Note that this group does not contain the volatile alka- 
loids — nicotine, coniine, sparteine. Because the solution is 
acid, salts of the alkaloids are formed, and these are not volatile. 
Before distilling, certain preliminary tests are made. These 
may shorten or obviate the necessity of much work. 

Preliminary Test for Phosphorus 
Scherer's test. 

This is founded on the fact that phosphorus in a solution of 
silver nitrate, acidified with nitric acid, forms silver phosphide 
(Ag 3 P). 

The vapor of phosphorus will give this test with filter paper 
moistened with the silver nitrate solution. Hydrogen sulphide 
will also darken silver nitrate so a control test must be made along 
with the preliminary test, as follows: (See Fig. 3.) 

Place some of the solution to be tested in a distillation flask, 
with a cork stopper. Moisten a strip of filter paper about 
6-10 cm. along, and 1 cm. in width, with the silver nitrate solu- 
tion, and insert this in a V-shaped slit in one side of the cork, 
moisten another, similar piece of paper, with lead acetate, and 
place this in a slit in the other side of the cork. Be sure that the 
papers do not touch each other. Place the cork in the flask, 
and set the flask on a water bath at about 50°C. 

It is advisable to protect the papers from light, since light 
colors the silver to some degree 1 . 

Discussion of Results 

(a) If the silver paper only is darkened phosphorus may be 
present. 



TOXICOLOGY 



383 



(b) If both papers are darkened H 2 S is also present, and in 
either case the test for phosphorus should be made. Any 
volatile organic reducing substance such as formaldehyde or 
formic acid may also darken the papers. 

(c) If neither paper is darkened, phosphorus is absent and 
further tests for phosphorus need not be made. The preliminary 
test is more important therefore in establishing the absence of 
P. than its presence. 





Fig. 3. — (After Autenrieth-Warren.) 



Fig. 4. 



Principal Test for Phosphorus 

I. Mitscherlich's Test. — In examining animal material such as 
stomach and contents, liver, spleen, kidney, etc. It is ground to 
a fine pulp in a mortar, a little clean sand may be used, and 
placed in a flask of suitable size, sufficient water is added to give 
it a mash like consistence. The flesh present may be cut with 
scissors to about the size of peas before grinding. If the pre- 
liminary test does not rule out P. set up a distillation apparatus 
as in Fig. 4. 

The glass tube in this case should be about 130 cm. long, 45 
high and about 8 mm. internal diameter. The lower end of the 
tube from the condenser should dip one or two centimeters under 
water in the flask C to collect any gases like HCN that may come 
over in the distillate. If yellow phosphorus is present a character- 



384 



CHEMICAL PHARMACOLOGY 



istic phosphorescence appears in the tube — and may be seen 
best in a dark room or when the distilling apparatus is covered 
with a black cloth. The phosphorescence is due to oxidation of 
the phosphorus. It may be prevented or masked by alcohol, 
ether, formaldehyde, formic acid, chloroform, chloral hydrate, 
benzin, petroleum, turpentine, ethereal oils, hydrogen peroxid, 
mercuric chlorid, phenol, creosote, hydrogen sulphide, and putre- 
factive products. When the presence of P. is established by the 




Fig. 5. — (After Kippenberger.) 

phosphorescence, it is advisable to let the apparatus cool, and 
change the distillation to the regular Liebig condenser, see Fig. 6. 

In heating organic matter in a flask over a free flame, there is 
danger of breaking the flask, consequently some advise the 
heating on a water bath or on an oil bath. Again in heating the 
flask in presence of oxygen some of the phosphorus may be 
oxidized to P 2 5 which is not volatile, and to prevent this some 
advise distillation from an atmosphere of C0 2 , see Fig. 5. 

To test for phosphorus in the distillate, add an excess of 
chlorine water, or fuming nitric acid and evaporate to dryness 



TOXICOLOGY 



385 



on a water bath. This oxidizes the phosphorus to H3PO4. 
Acidify with a few drops of HN0 3 and dissolve in 10 cc. water. 
Use 5 cc. for each of the following tests. 




Fig. 6. 



(After Autenreith-Warren.) 



I. Ammonium Molybdate Test. — Add 5 cc. of the solution to be 
tested to 5 cc. ammonium molybdate solution and warm on a 
water bath at 40°C. A yellow precipitate of ammonium phospho- 
molybdate is formed. 




Fig. 7. — (After Kippenberger.) 

II. Ammonium Magnesium Phosphate Test. — Add an equal 
volume of magnesia mixture to 5 cc. phosphate solution. Be sure 
the solution is slightly alkaline. Ammonium magnesium phos- 
phate is precipitated (NH 4 ) Mg.P0 4 .6H 2 0. 

The precipitate is formed slowly and is facilitated by shaking. 
Let stand over night if necessary. 

25 



386 



CHEMICAL PHARMACOLOGY 



In an elementary course in toxicology where the object is 
training in principles only, quantitative work is unnecessary, 
yet in many cases quantitative work is of more value as an aid to 
correlation and assimilation, than qualitative work. 

The Mitscherlich-Scherer Method for the Qualitative and 
Quantitative Estimation of Phosphorus. — A weighed portion of 
the substance to be analyzed, is placed in flask and acidified with 
H 2 S0 4 , and a little ferrous sulphate added. This last is added to 







1 c 

Fig. 8. — (After Autenreith-Warren.) 

prevent oxidation of the P. Before heating the air is expelled 
from A, by C0 2 , from the Kipp generator E. The C0 2 is washed 
with water in F. C contains water, and D contains a silver nitrate 
solution. The stop-cock B permits the entrance of air, if desired 
to increase the phosphorescence. When this has been seen no 
more air is admitted. The P collected in C is oxidized with bro- 
mine water or HN0 3 , on a water bath and evaporated to dryness. 
The P. is oxidized to phosphoric acid. This is precipitated with 
magnesium mixture, filtered, dried, ignited and weighed as 
magnesium pyrophosphate, Mg 2 P 2 7 . 



TOXICOLOGY 387 

The P. in the silver nitrate in D as Ag 3 P is heated with nitric 
acid which oxidizes the P. The silver nitrate is precipitated and 
removed as AgCl by the addition of NaCl. This is filtered off, 
and the filtrate treated as the contents of C and added to C. 

This method will detect .00006" gram of yellow phosphorus. 

Detection of Phosphorus in Oils 

Straub's Test/ — Copper sulphate in contact with phosphorus, 
forms copper phosphide Cu 3 P2(?) and at the same time tends to 
oxidize the phosphorus. Because of this copper sulphate is 
used in the treatment of phosphorus poisoning. 

Test. — In a test tube shake equal volumes of oil containing 
phosphorus and 1 per cent, copper sulphate. A black emulsion 
is formed, or a black ring at the junction of the liquids when the 
emulsion settles. 

ACETONE 

Acetone is not an important poison. To test for its presence 
in the distillate use tests, page 63. 

ANILINE 

For tests see page 113. 

OIL OF BITTER ALMONDS OR BENZALDEHYDE 

See pages 76 and 104. Pure benzaldehyde is not poisonous, 
but it occurs in oil of bitter almonds in the form of the cyan- 
hydrin of benzaldehyde 

C 6 H 5 - C— OH 

\CN 

This is readily hyclrolyzed by KOH into -> KCN + H 2 + 
C 6 H 5 CHO. (Benzaldehyde.) 

Test for KCN. — To 2 cc. oil of bitter almonds or the same 
volume of the distillate add 10 cc. KOH 5 per cent., heat gently, 
add a few drops of freshly prepared ferrous -sulphate containing 
a drop or two of ferric chloride. Prussian blue is formed. See 
test for nitrogen, page 8. To test for benzaldehyde : add KOH 
to the original solution. Extract with ether in a separatory fun- 
nel, remove and evaporate the ether on a water bath at 40°C. 



388 CHEMICAL PHARMACOLOGY 

If benzaldehyde is present it is deposited as globules. Heat 
these globules with 10 cc. 5 per cent, potassium dichromate and 
dilute sulphuric acid under a reflux condenser. The benzalde- 
hyde is converted into benzoic acid. Cool the liquid and again 
extract with ether. Evaporate the ether. Benzoic acid remains, 
its melting point is 120°-121°C. When dissolved in dilute 
NaOH, ferric chloride produces a flesh colored precipitate. 

CARBON BISULPHIDE 

Carbon bisulphide distils slowly with steam and is found 
but little in the first third of the distillate. 

I. Lead Acetate Test. — CS 2 is not precipitated by lead until 
after decomposition. Add an equal volume of lead acetate to 
CS 2 shake — no reaction. Now add an excess of KOH and boil. 
A black precipitate of Pb.S will appear (cf. H 2 S). 

II. When an aqueous solution of carbon bisulphide is heated 
with an alcoholic solution of NH 4 OH — ammonium sulphocyanate 
is formed together with ammonium sulphide. Evaporate 
nearly to dryness on water bath to expel (NH 4 ) 2 S. Dissolve in 
dilute HC1. When ferric chloride is added to this a deep red 
color due to iron sulphocyanide appears. .05 gram of CS 2 
will give this test. 

The reaction is : 

1 4NH 3 + CS 2 - (NH 4 ) CNS + (NH 4 ) 2 S 

2. FeCl 3 + 3(NH 4 )CNS = Fe (CNS) 3 + 3NH 4 C1 

III. Xanthogenate Test. — When CS 2 is shaken with 3-4: times 
its volume of saturated alcoholic KOH it gives potassium xantho- 
genate as follows : 

SK 



CS 2 + C 2 H 6 OK = C = S 

\ 



OC 2 H b 



This is a yellow compound, when this is acidified with acetic 
acid and copper sulphate added, a black precipitate of cupric 
xanthogenate is formed. 



TOXICOLOGY 389 

SK S 

/ / 

2C = S + CuS0 4 = (S = C \ Cu H ■ K 2 S0 4 

\ \ 

C 2 H 5 O C 2 H 5 

The cupric xanthogenate then decomposes into cuprous 
xanthogenate and ethyl xanthogen disulphide, as follows: 
OC2H5 OC2H5 OC 2 H 5 





S = C 


s = c s = c 




\ 


\ \ 




s 


S S— Cu 




\ 


1 + 1 


2 ■ 


Cu = 


S^ S— Cu 




/ 


V / 




s 


s = c s = c 




/ 


\ \ 




s - c 


\ \ 




\ 


OC 2 H 5 OC 2 H 5 




[ OC 2 H 5 


" 




Ethyl Cuprous 


Cupric 


— -> xanthogen + xanthogenate 


xant 


logenate 


disulphide 



Chloroform: Tests see p. 42. 
Introduce 5 cc. chloroform into flask a (Fig. 7) ; heat on a water 
bath and blow current of air through the flask and through the 
heated tube c. This decomposes the chloroform vapor with 
formation of HC1, which can be demonstrated by collecting it in 
the U tube d. which contains a one per cent, solution of AgN03. 

CHLORAL HYDRATE 

Chloral hydrate distils very slowly with steam. The solution 
should be distilled for a long time and quite completely in order 
to get most of it over. It is decomposed by distillation. For 
tests, see page 60. 

ETHYL ALCOHOL 

This would be present in the same distillate as methyl alcohol. 
It is quite impossible to separate them but tests for each may be 
made. For tests see page 23. 



390 CHEMICAL PHARMACOLOGY 

METHYL ALCOHOL 

This would be all distilled over when one third of the original 
volume is distilled. For tests see page 18. 

IODOFORM 

Iodoform distils readily with steam giving a milky distillate 
which may be recognized by its odor. For "tests and reactions 
see page 80. 

NITROBENZENE 

C 6 H 5 N0 2 . The boiling point of this oily liquid is 208°C. 
which is higher than that of phenol (183°C.) consequently most 
of it will appear in the last part of the distillate: It is nearly 
insoluble in water but very soluble in ether and if only traces are 
present, the distillate should be shaken with ether, the ether 
evaporated at about 40°C. and tests made on the residue. For 
tests see page 110. Convert it into aniline, by reduction with 
hydrogen and then make the aniline tests, page 112. 

PHENOL 

Phenol boils at about 180° and distils readily with steam. The 
distillate may be cloudy and is recognizable by its odor, though 
this may be masked by putrefactive odors. Traces of phenols 
are formed in all putrefactions. For tests see page 99. 
Quantitative Estimation of Phenol 

An excess of saturated bromine water precipitates phenol in 
aqueous solution as tribromophenyl hypobromite — C 6 H 2 Br 3 OBr. 

Method. — Place an aliquot part of the liquid under examina- 
tion in a stoppered flask. Add bromine water from time to time 
and shake until the supernatant liquid has a red brown color and 
bromine vapor is visible above the liquid. Let stand 2-4 hours 
and filter through a weighed Gooch crucible. Dry in a desiccator 
over H 2 S0 4 to constant weight. The weight of the dried precipi- 
tate multiplied by 0.2295 gives the amount of phenol, since 
C 6 H 2 Br 4 Q . (\,H,OII 94.05 
409.86 " 94.05 409.86 

CREOSOTE (Creosols) 
See page 96. Creosotes arc methyl phenols and distil over 
similar to carbolic acid. Some commercial creosotes contain 



TOXICOLOGY 391 

phenol. The tests are in many cases similar to phenol and hard 
to distinguish from it. 

1. With pure creosote iron chloride gives a green color, while 
with phenol it gives a blue-purple color. 

2. HN0 3 when added to creosote gives picric acid, HN0 3 does 
not form picric acid directly with phenol. 

3. When equal volumes of colloidon and creosote are shaken 
together there is no visible change while with phenol, a gelatinous 
coagulum is formed. 

NON-VOLATILE ORGANIC POISONS 

Before non-volatile organic poisons can be extracted from 
stomach contents, organs, etc. the proteins, fats, carbohydrates 
and resinous material must be removed. As an aid to their 
removal and to lessen the likelihood of removing poisons with 
these materials, the organs are cut, or ground so that no piece is 
larger than a pea. The finely chopped material is then placed 
in a flask of suitable size and three times the volume of absolute 
alcohol which has been redistilled from tartaric acid is added. 
The alcohol has been redistilled to remove basic material which 
often is present in commercial alcohol. Just enough tartaric 
acid is added to acidify the mixture. The whole is extracted on 
a water bath for 30 minutes using a reflux condenser. Cool the 
flask and contents, in order to help solidify fats present, and 
filter through cheese cloth if much solid material is present. 
Wash with absolute alcohol, and filter through paper to remove 
fat and solid matter. Wash again with alcohol. Evaporate the 
filtrate in a glass or porcelain dish on a water bath to a syrupy 
consistency, and thoroughly mix with about 100 cc. water. 
This precipitates resins. Filter, wash with water and again 
evaporate to a syrup. Mix thoroughly with 150 cc. absolute 
alcohol. This precipitates proteins, albumoses, peptones, dextrin- 
like bodies, some inorganic salts — while the tartrate salts of the 
poisons are dissolved. Filter and wash with alcohol. Again 
evaporate off the alcohol and dissolve the residue in about 50 cc. 
of water. This should be relatively clear and free from proteins, 
fats, carbohydrates and resins, but if not the above processes 
should be repeated until a clear solution is obtained. This is 
the most important part of the analysis, as upon the removal 



392 CHEMICAL PHARMACOLOGY 

of all foreign matter depends the success of the tests which follow. 
At all stages the solution should be acid — but a large excess of 
acid should be avoided as its presence interferes with the tests. 
When the solution is so prepared it is ready for the Stas-Otto 
method of extraction. This method consists in extraction of 
the poisons with immiscible solvents first with acid alcohol, then 
changing the solvent to water solution; and then successive 
extractions of the prepared liquid with ether and chloroform in 
acid and alkaline reactions as given below. 

Acid Extraction — Stas-Otto Method. — Place a portion, or all, 
of the prepared acid extract in a separatory funnel. Add an 
equal volume of ether, shake well, allow to settle and remove the 
ether into an evaporating dish. Repeat the extraction 3 or 4 
times. Unite all extracts and allow to stand for 30 minutes. If 
water separates out, it may be removed by filtering through 
a dry filter. A dry filter will absorb and retain considerable 
water. Evaporate the ether at a temperature of 40°C. Since 
only a small residue may be expected after evaporation, 
it is best not to have this spread over a large surface. To avoid 
this let the ether extract drop from a separatory funnel into a 
small evaporating dish at a rate about equal to the evaporation. 
In this way whatever residue remains is on a small surface and 
more easily examined. The completion of the evaporation may 
be carried out on a water bath at a higher temperature if the 
residue remains too moist for examination. 

Even when none of the first group of poisons is present, some 
little residue may remain which consists of tartaric acid, lactic 
acid, resins, etc. which are not completely removed in the process. 

The residue may contain any of the following poisons. 

Acetanilide Caffeine 

Antipyrine Picrotoxin 

Phenacetine Picric acid 

Salicylic acid Veronal 

Colchicine 

Also traces of mercuric cyanide: 

Cantharidin 

Digitalin 

Veratrine 



TOXICOLOGY 393 

and Atropine may occur in this extraction. An examination of 
the general appearance, taste, odor, color, etc. of the residue should 
be made. Then a microscopic examination for crystals should be 
made. Since usually only one of the poisons of the group is 
expected, tests for the most likely should be made first. 

II. After the acid solution has been extracted with ether, it is 
made alkaline with sodium hydroxide. The alkali liberates most 
alkaloids from this salts, and these are then readily extracted 
with ether. Morphine, apomorphine, and narceine are more 
soluble in the water alkaline solution than in ether, consequently 
are not extracted, with ether. Note this exception to the general 
alkaloidal solubilities. The water solution should be saved for 
further investigation. The ether extract from alkaline sodium 
hydroxide should be "examined for : 

Page Page 

Aniline 112 Narcotine 265 

Antipyrine 119 Nicotine. . 255 

Atropine 272 Physostigmine 295 

Brucine 257 Papaverine 283 

Caffeine 288 Pilocarpine 275 

Cocaine t 267 Pyramidone 119 

Codeine 281 Quinine 261 

Coniine 252 Scopolamine 272 

Hydrastine 263 Strychnine 257 

Thebaine 282 

Veratrine 294 

The figures refer to pages in the text where the tests are 
given. 

III. The alkaline sodium hydroxide solution, after extraction 
with ether, is slightly but distinctly acidified with tartaric or 
sulphuric acid. Then made alkaline with ammonia, and ex- 
tracted in a separatory funnel with ether, and afterwards with 
chloroform. 

A. The ether extract may contain, apomorphine and traces of 
morphine. 

B. The chloroform extract may contain morphine, narceine 
and antipyrine and caffeine that was not previously removed. 



394 CHEMICAL PHARMACOLOGY 

METALLIC POISONS 

To detect poisonous metals, in animal or vegetable matter, 
it is first necessary to destroy or remove the organic material 
after which the tests -are made in the same way as in inorganic 
chemistry. In toxicological analysis therefore a most important 
part of the process is the removal of the organic material. 

Method 

Various methods may be used, the principle in all is essentially 
the same. The Fresinius v. Babo method is taken as the type. 
Since all the organic poisons are also destroyed when the organic 
matter is being destroyed, one may work either with an orig- 
inal portion of the material or with the residue that remains 
after the organic poisons have been removed. A portion of 
the material is mixed to a fluid mass and placed, in a large 
flask Fig. 9. 

About 30 cc. concentrated HO is added per 100 cc. mate- 
rial, and 1-2 grams of KC10 3 added. The flask is heated on 
a boiling water bath in a hood. Nascent chlorine is evolved 
which destroys the organic matter. When the flask is hot, it 
is frequently shaken and a trace of KCIO3 added from time to 
time until the solution is a pale yellow color and longer heating 
produces no further change. Fat is very resistant to oxidation in 
this way, yet is easily oxidized in the body. 

When oxidation is complete dilute with hot water and add a 
little sulphuric acid to precipitate possible barium, filter and 
evaporate in a porcelain dish on a water bath nearly to dryness 
to remove excess of acid. The decomposition of some KC10 3 
may give a brown color at this point. If necessary filter, wash 
with water and evaporate again almost to dryness. Dissolve 
in water, and filter. There will be some insoluble white residue 
wholly unaffected by the action of chlorine (see test for Ba). 

Examination of Filtrate 

This should have only a faint yellow color, and be slightly acid. 
Place in a flask and heat on a water bath. While heating saturate 
the solution with H 2 S from a Kipp generator. The gas should 
be run for 30 minutes in the hot solution, and again for 30 min- 
utes after the flask has cooled, then the flask is tightly stoppered 



TOXICOLOGY 



395 



and allowed to stand for several hours — preferably over night — 
and filtered. The filtrate may contain chromium or Zn. The 
precipitate may contain As, Sb, Sn, Cu, Hg, Pb, Bi, Cu, Cd. 




Fig. 9.— (After Autenreith.) 

Examination of the Precipitate 

The precipitate is thoroughly washed with hydrogen sulphide 
water, then the moist precipitate is dissolved in about 25 cc. of 
a mixture of equal parts of ammonium hydroxid and yellow 
ammonium sulphide and heated to boiling — filter and wash 
several times with some of the hot ammonium — sulphide mixture : 
The filtrate may contain As, Sb, Sn, or Cu. The precipitate 
Hg, Pt, Bi, Cu or Cd. 



396 CHEMICAL PHARMACOLOGY 

i 

Examination of the Filtrate 

Evaporate the solution to dryness on a water bath — cool, 
moisten with HN0 3 and again evaporate to dryness. Then mix 
the residue with 3 times its volume of a mixture containing 2 parts 
sodium nitrate and 1 part sodium carbonate. Evaporate this 
mixture to dryness and add it little by little to a crucible contain- 
ing a little sodium nitrate heated to redness. The heating is 
continued until the whole is fused. If copper is present the melt 
is gray or black. Sodium arsenate, sodium pyroantimonate and 
sodium stannate may also be present. When the crucible is 
cold, add a little hot water and wash into a flask. If sodium 
stannate is present a little sodium bicarbonate is added to 
precipitate the tin as stannic oxide. Filter. The filtrate may 
contain As as sodium arsenate and the residue will contain 
sodium pyroantimoniate (Na2H 2 Sb 2 07), stannic and copper 
oxides. 

Arsenic Test 

Acidify the filtrate with arsenic free sulphuric acid. Evaporate 
over a free flame, and add sufficient sulphuric acid to expel nitric 
acid. Heat until copious white fumes of sulphuric acid appear. 
Arsenic if present is in the form of arsenic acid and is tested in the 
Marsh Apparatus, see Fig. 10 (Autenrieth, Warren). 

Place 30 grams of arsenic free zinc in flask A. Pour 15 per 
cent, arsenic free sulphuric acid on the metal. The flask should 
be kept cool during the analysis by keeping it surrounded with 
cool water and by generating hydrogen slowly. If the tempera- 
ture gets too high S0 2 is formed and this in presence of hydrogen 
is reduced to H 2 S, which interferes with the test. All joints of 
the apparatus should be tight to avoid escape of AsH 3 and also to 
prevent explosions. Air should be completely expelled before 
igniting also to prevent explosion, to determine whether the air is 
expelled catch some of the escaping hydrogen in a test tube and 
test from time to time until it ignites without detonation. It 
may require 10 minutes to expel the air. When lighted and 
before adding the solutions to be tested, one should test to see 
that no arsenic is present in the chemicals. If the hydrogen is 
arsenic free, the solution to be tested is gradually introduced into 
the sulphuric acid — zinc flask, A, through the funnel — at the 



TOXICOLOGY 



397 



same time the tube C. is heated to redness just back of the 
constriction D. If the solution contains As, a shining metallic 
arsenic mirror is deposited, just beyond the point of ignition. 

2. If the flame is removed from C. and a cold porcelain dish 
pressed down on the arsine-hydrogen flame a brownish black 
spot is formed upon the dish. This spot dissolves readily in sodium 
hypochlorite solution. Antimony spots will not dissolve. 

3. If the hydrogen flame is extinguished, and the end of the 
tube dipped into a dilute silver nitrate solution, arsine produces 
a black precipitate of metallic silver. 




4. Arsine produces a yellow stain on a piece of filter paper 
moistened with cone, silver nitrate solution. A drop of water 
added to this changes the yellow spot to black. This is Gutzeit's 
test. 



Detection of Antimony 

The insoluble residue after fusion may contain Cu, Sb, or Sn. 

1. Test for Cu. — Dissolve in dilute HC1. The solution may 
be colored light blue, excess of NH 4 OH produces a deep blue 
color. Potassium ferrocyanide gives a deep red precipitate. 

Test for Tin. — The insoluble residue is dissolved in HC1 as 
in testing for copper. The tests for tin depends on the fact 
that tin chloride is a reducing agent. 

1. Add a few drops of mercuric chloride. If tin is present it 



398 CHEMICAL PHARMACOLOGY 

reduces this to calomel which precipitates. When heated this 
precipitate is changed to metallic mercury. 

Test for Antimony 

Dissolve in dilute hydrochloric acid by aid of heat. Introduce 
into Marsh gas apparatus and test in the same way as for arsenic. 

1 . Differences between Arsenic and Antimony. — The antimony 
mirror in the Marsh gas apparatus is deposited on both sides of 
the flame. The metal in contact with the heated flame fuses 
to the glass and is silver white. It sublimes with difficulty. 
Arsenic volatilizes readily. 

2. Nitric acid dissolves both antimony and arsenic mirrors. 
When neutralized with ammonium hydroxid, silver nitrate 
precipitates silver arsenate Ag 3 As0 4 which is reddish, with 
antimony there is no reddish precipitate. 

3. The spot produced on a cold porcelain surface when held 
to the Marsh gas flame by arsenic is not heavy, is brown and 
lustrous, and dissolves readily in sodium hypochlorite. 

The antimony spot is heavy velvet like, not lustrous and is 
insoluble in hypochlorite. 

Detection of Metals Whose Sulphides are Insoluble in Ammonium 

Sulphide 
This group includes: 

Bismuth Copper 

Cadmium Lead 

Mercury 

1. Treat these sulphides on the filter with dilute nitric acid. 
All dissolve except mercury — save the filtrate for further work. 

Test for Mercury. — dissolve the sulphide with hot dilute HC1 
containing a crystal of potassium chlorate. Filter, evaporate 
to dryness on a water bath, and dissolve in 5 cc. 5 per cent. HC1, 
filter and test filtrate for mercury, as follows : 

1. To a portion add a few drops of stannous chloride. The 
mercuric chloride is reduced to calomel which is precipitated. 
Excess of stannous chloride especially if heated reduces the calo- 
mel to metallic mercury. 

2. Place a few drops of the solution to be tested on a piece of 
clean copper. A gray spot with silver luster is deposited if 



TOXICOLOGY 399 

mercury is present. Wash with water, alcohol, and ether, dry 
and place the copper in a small test tube. Heat over free flame. 
Mercury sublimes and collects in metallic globules on the cool 
sides of the tube. A crystal of iodine placed in the warm tube 
vaporizes and scarlet mercuric iodide is formed. 

3. Dilute potassium iodide added to a solution of HgCl 2 pre- 
cipitates the red iodide Hgl 2 . 

Examination of the Nitric Acid Solution 

This may contain Pb, Cu, Bi and Cd nitrates. 

Evaporate to dryness and dissolve in a little hot water, add 
dilute sulphuric acid. Lead precipitates — -filter. The sulphates 
of Cu, Bi and Cd are soluble. Test the filtrate for these. 

Copper and Bismuth Tests. — Add excess of ammonium hy 
drate, if Cu is present it produces a blue color. If Bi is present, 
it is precipitated as Bi(OH) 3 . Filter dissolve ppt. in dilute HC1. 
Pour into 50 cc. water. A white precipitate of BiOCl proves the 
presence of bismuth. If cadmium be present, it will give a 
yellow precipitate with hydrogen sulphide. Jf present with 
copper, add solid KCN to the blue color, until the color dis- 
appears. 

Then pass hydrogen sulphide. The copper remains in solu- 
tion. As K 4 Cu 2 (CN) 6 while yellow CdS is precipitated. 

CHROMIUM AND ZINC 

If present these are found in the H 2 S filtrate. 
Detection of Zn 

Make one half of the filtrate alkaline with ammonium hydrate 
and add ammonium sulphide. This will precipitate Zn, but 
there may be a precipitate even if no Zn is present, because 
solutions from animal matter contain traces of iron, alkaline 
earths, phosphates, etc. Add acetic until faint acid reaction; 
this dissolves phosphates except ferric phosphate. Filter, wash 
with water, dry and ignite in porcelain crucible. A drop of 
ammonium nitrate aids oxidation — cool. Add dilute sulphuric 
acid, boil and filter. This converts Zn into ZnS0 4 — divide the 
filtrate into two equal parts. 

(a) Add dilute NaOH to precipitate iron which may be present 



400 CHEMICAL PHARMACOLOGY 

as ferric phosphate. Filter, add a few drops of ammonium sul- 
phide. This precipitates ZnS as a white flocculent precipitate. 
(6) Add ammonium hydroxide and filter to remove ferric 
phosphate. Acidify filtrate with acetic acid. Zn if present can 
be precipitated with hydrogen sulphide as a white precipitate. 

Detection of Chromium 

Evaporate a portion of the hydrogen sulphide filtrate almost to 
dryness, add about 1 gram each of sodium carbonate and potas- 
sium nitrate — dry and add ,a Jittle at a time to a hot crucible 
containing fused potassium nitrate. Heat until fusion is com- 
plete. This oxidizes chromium to chromates. Cool and dis- 
solve in water, and filter. The filtrate is yellow if chromium is 
present, acidify with acetic acid and add a little lead acetate; 
yellow lead chromate is precipitated. 

Detection of Lead, Silver and Barium 
The residue from the fusion with potassium chlorate may con- 
tain lead, silver or barium. The residue is dried in an air oven, 
and ground in a mortar. Then 3 times the amount of a mixture 
of potassium nitrate and sodium carbonate is added and the 
mixture fused in a crucible adding a little potassium nitrate to 
complete the fusion. This destroys fats and other organic 
matter. Cool and dissolve in water. Transfer to a flask and 
pass CO2 through the flask. The precipitates lead as the car- 
bonate. Filter, the precipitate may contain lead and barium 
carbonate and metallic silver and silver oxide. This silver gives 
the precipitate a gray color. Wash with water and dissolve in 
dilute nitric acid. Evaporate to dryness and dissolve in hot 
water. Add HC1 and heat, this precipitates silver, filter and 
add H 2 S to precipitate lead. Filter and heat to expel the excess 
of H 2 S. Add dilute H 2 S0 4 to precipitate barium. The con- 
firmatory tests need not be given. 

SYNOPSIS OF METALLIC POISONS 

The material is boiled with dilute hydrochloric acid (about 
12 per cent.) and potassium chlorate added until a pale yellow 
solution results. This destroys organic matter and dissolves the 
heavy metals. A little sulphuric acid is added and the solu- 
tion filtered. 



TOXICOLOGY 



401 



Filtrate may contain — As, Sb, Sn, Cu, 
Hg, Pb, Bi, Cu, Cd, Cr, Zn. 
Add H 2 S 



Precipitate may — con- 
tain — Pb, Ag, Ba. 



Precipitate — Dissolve precipitate with 
yellow ammonium sulphide and am- 
monium. Filter. 



Filtrate contains — Cr 
and Zn. 



Filtrate contains- 
As, Sb, Sn, Cu. 



Residue — Hg, Pb, 
Bi, Cu and Cd. 



SULPHURIC ACID 

Sulphates are present in small amounts in all vegetables and 
animal matter. The appearance of the tongue and stomach as 
well as the amount after sulphuric acid poisoning should settle 
any case of doubt. The tongue may be dark or boiled looking 
due to the formation of methemoglobin, hematin, etc. 

I. The finally divided stomach and tissues reacts strongly 
acid. When extracted with water and filtered, the filtrate is acid. 

II. The barium chloride gives a precipitate which is insoluble 
in HC1. The amount of H 2 S0 4 may be determined by igniting 
the precipitate, and weighing in a weighed crucible or by titra- 
tion of the water extract as under HC1. 

III. When the water extract is evaporated on a water bath 
and then over a free flame white fumes of S0 2 are evolved. A 
particle of sugar, or any organic matter added to this heated 
solution will be carbonized. 

Nitric Acid. — Nitrates occur only in traces in foods and or- 
ganic matter. In a case of poisoning with nitric acid, the parts 
of the body touched by it are yellow — xantho-protein test. If 
taken in dilute form nitric acid is excreted in the urine as nitrates. 

Tests 

I. The water in extracts gives the tests for mineral acids. 

II. It distils after it reaches a certain concentration. The 

26 



402 CHEMICAL PHARMACOLOGY 

protein material in the distillation flask is yellow — xantho-pro- 
tein. If distillation is carried far enough, the brown vapors of 
nitrogen peroxid appear. 

III. Brucine test: Mix part of the distillate with an equal 
volume of a solution prepared by mixing 1 gram brucine in 5 cc. 
dilute sulphuric acid and 95 cc. water. Pour this mixture care- 
fully on concentrated sulphuric acid in a test tube. If nitric 
acid is present, a black ring is formed between the solutions. 

IV. Saturate the liquid to be tested with ferrous sulphate. Pour 
this upon concentrated H 2 S0 4 . A black zone appears between 
the liquids. 

V. Nitric acid evolves red brown vapors of NO2 when clean 
metallic copper is added. 

OXALATES AND OXALIC ACID 

Extract the finely divided material with 3-4 volumes of hot 
absolute alcohol acidified with HC1. Cool to about 10°C. and 
filter through dry paper. Fats and proteins are removed. Add 
20 cc. water to prevent the formation of ethyl oxalate and evapo- 
rate the alcohol. The residue may again be extracted with, 
alcohol and evaporated. Make alkaline with ammonia, filter 
if there is a precipitate and to the clear filtrate add calcium 
chloride solution. A precipitate of octahedron crystals or en- 
velope shaped crystals of calcium oxalate results. These should 
be examined under the microscope. If it is desired to determine 
the amount of oxalic present, this may be done by igniting the 
precipitate in a weighed crucible as CaO. 

CaO:H 2 C 2 042H 2 : : 56 : 126 
56 :126 = 0.444 

Consequently the weight of the precipitate multiplied by 0.444 = 
gives the amount of oxalic acid. 

To get purer crystals of calcium oxalate, for identification, it 
is sometimes advised to extract the water solution from the 
alcohol filtrate with ether, and use the residue after evaporation 
for the test. This gets rid of some interfering bodies which may 
be present in the alcohol extract. 



TOXICOLOGY 403 



ALKALIES 



The tissues after alkali intoxication react blue to litmus and are 
soft and greasy, if poisoning has occurred from ammonia it may 
be recognizable by its odor. To detect ammonia, or to estimate 
the amount, it will be sufficient to extract with water, filter — ■ 
add 20 cc. strong NaOH and distil. The distillate reacts alkaline 
and the amount may be titrated with N/1 NaOH, using cochineal 
as the indicator. 

FIXED ALKALIES 

Extract with water, filter. The filtrate reacts alkaline, the 
fingers moistened with it feel slimy. The amount may be 
titrated with N/1 acid using phenolphthalein as the indicator 
and alcoholic extract of the tissues shaken with freshly precipi- 
tated washed mercurous chloride gives a black compound, which 
is soluble in nitric acid. 

POTASSIUM CHLORATE 

I. Extract the tissues with water and filter, add excess of silver 
nitrate and filter if there is a precipitate; add a little sul- 
phurous acid and heat. If chlorate is present this decomposes 
it with the formation of a chloride, which gives a precipitate with 
the excess of AgN0 3 in the solution: 

AgC10 3 + 3H 2 S0 3 = AgCl + 3H 2 S0 4 
Add dilute HN0 3 — silver sulphite dissolves, if present, silver chlo- 
ride is insoluble. 

II. Chlorates liberate chlorine from hydrochloric acid and the 
gas will liberate iodine from potassium iodide. 

(a) Heat a solution containing a chlorate with concentrated 
HO— free chlorine is given off. Pass the gas into a solution of 
potassium iodide; free iodine is liberated and can be separated 
by dissolving in chloroform. 

Chromic acid and bichromates also liberate chlorine from 
hydrochloric acid. 

ACTIVE SUBSTANCES WHICH MAY CAUSE POISONING, BUT 

WHICH ARE HARD TO DETECT, AND WHICH FIND NO 

PLACE IN THE STAS-OTTO METHOD 

Cantharidin is the vesicating principle of Spanish fly. 
Chemically it is the anhydride of cantharidic acid. 



404 



CHEMICAL PHARMACOLOGY 



H 


H 




C CH 2 - COOH 


C CH2- 


-COOH 


/ 


\/ 


/ 


V 




1 2 C 


C— OjH = 


H 2 C 


C— 


+ H 2 


| CH 2 | 


| CH 2 | 




hC \C — CO !OH 


h 2 c \c-eo 




\ / 


\ / 




c 


c 




H 2 


H 2 




Cantharidic acid 


Cantharidin 





It occurs as small, colorless glistening crystals which melt at 
214°-218°C. and sublimes at higher temperatures in white 
needles. The pharmacopeia gives a method for the extraction 
of the active substance from Spanish fly. There is no chemical 
test for it. The physiological test consists in dissolving a little 
of the substance in a fatty oil and rubbing it on a spot on the arm 
or chest. A blister will be formed in a short time if cantharidin 
be present. 



SANTONIN, SULPHONAL, TRIONAL 

These substances are not extracted under the conditions of the 
Stas-Otto process. They are not soluble in acid ether solution. 
Extract the tartaric acid solution of the organs with hot alcohol, 
filter. If a colored solution results add a little animal charcoal 
and heat again. Filter while hot, cool and extract the acid 
solution several times with chloroform. Evaporate the chloro- 
form which may contain sulphonal, trional, santonin. 

1. Santonin, see page 220. 

2. Sulphonal, see also page 46. 

3. Trional, see page 46. 

Cytisine is an alkaloid of unknown structure, CnHi 4 ON 2 , 
found to the extent of 1.5 per cent, in the ripe seeds of Golden 
Chain — Cytisus Laburnum. Cytisine forms large colorless 
rhombic crystals which melt at 153°. It causes convulsions 
similar to strychnine, but it is also irritating to the gastrointesti- 
nal tract, and for this reason may cause vomiting, and it also 
stimulates the vomiting center directly. Cytisine also resembles 
nicotine in action. In the tartaric extract in the Stas-Otto 



TOXICOLOGY 405 

method, it can be extracted with chloroform in alkaline solu- 
tion of NaOH. 

Test I. — Ferric chloric! colors cytisine and salts blood red. The 
color is discharged by hydrogen peroxid which changes to blue when 
heated on water bath. 

Test II. — Nitrobenzene containing dinitro-thiophene pro- 
duces a reddish violet coloration. 

Digitalis. — Nothing is known regarding the fate of digitalis in 
the body, consequently extracts of the tissues cannot be tested 
chemically for it. It has been claimed that more of it accumu- 
lates in the heart than in other tissues. This has been shown by 
physiological tests; no test for the drug as a whole is at hand. 

Digitonin when dissolved in sulphuric acid, gives a red color 
with bromine water. 

Digitoxin. — I. This dissolves in concentiated HC1, with a 
brownish green coloration, which is unchanged by the addition 
of bromine. 

II. Kiliani's test. Digitoxin dissolved in a little glacial acetic 
acid containing a trace of ferric sulphate. When superimposed 
on strong sulphuric acid containing a trace of ferric sulphate 
gives a dark ring. On standing the acetic acid layer becomes a 
deep indigo blue. 

Digitalin. — This dissolves in concentrated sulphuric acid with 
an orange yellow color, which changes to red on addition of 
bromine water, or ferric chloride, or after an hour with the 
addition of these oxidizing agents. 

ERGOT 

Ergot contains a red pigment — sclererythrin— which is charac- 
teristic of ergot. This cannot be found in tissues poisoned with 
ergot, but the material containing ergot, like flour, bread, etc. 
will give the following test. 

Test I. — If flour containing ergot be treated with a very 
dilute solution of anilin violet, the stain is absorbed by the 
damaged particles of the grain, while the normal particles are 
not stained. 

Test II. — Extract the flour with 10 to 15 times its volume 
of 40 per cent, alcohol heated to 40°. Filter and add basic lead 
acetate to the filtrate. Filter. Press the precipitate between 



406 CHEMICAL PHARMACOLOGY 

filter papers warm and add a few drops of saturated borax solu- 
tion. If ergot be present a red violet color appears. 

REAGENTS AND SOLUTIONS 

Ammonium Molybdate Solution for Phosphates. — Dissolve 
50 gm. of molybdic acid in 72 cc. cone, ammonia and 136 water; 
slowly and with constant stirring pour the solution into 245 cc. 
of nitric acid, cone, and 574 cc. of water. Keep this mixture in 
a warm place for several days. Decant and preserve in glass 
stoppered bottles. 

Barf oed's Reagent is prepared by dissolving 45 grams of neutral 
cupric acetate crystals in 900 cc. of water and filtering. Add 
6 cc. of 10 per cent, acetic acid to the filtrate and dilute to a 
liter. A portion of the reagent when heated on the water bath 
should show no reduction. 

Benedict's Qualitative Reagent for Glucose. 

Copper sulphate 17.3 gm. 

Sodium citrate 173.0 gm. 

Sodium carbonate, anhydrous 1000.0 gm. 

Dissolve the copper sulphate separately in about 150 cc. of 
water and add slowly to the filtered solution of the other two in 
about 800 cc, and make up to 1000 cc. 

Esbach's Reagent. — Dissolve 10 grams of picric acid and 20 
grams of citric acid in 1 liter of water. 

Fehling's Solution 

A. Copper sulphate 69 . 28 gms. 

Water 1000.00 cc. 

B. Potassium and sodium tartrate 346.0 gms. 

Potassium hydroxide 100. 00 gms. 

Water to 1000.00 cc. 

Mix equal volumes of A and B, and then add four volumes 
water just before using. This mixed solution does not keep well. 

Froehde's Reagent is a solution of molybdic acid in sulphuric 
acid prepared by dissolving 0.5 gram of molybdic acid in 100 cc. 
of hot, pure concentrated sulphuric acid. The solution should be 
colorless and it does not keep long. 

Gold chloride is used in a 3 per cent, aqueous solution. 



TOXICOLOGY " ' 407 

Iodine Solution, aqueous (LugoPs). — Dissolve five grams of 
iodine and ten grams of potassium iodide in about 20 cc. of water. 
When completely dissolved add a sufficient quantity of distilled 
to make the product weight 100 grams. 

Iodine solution ; alcoholic, about 1 gram of iodine in 100 cc. of 
alcohol (95 per cent.). 

Mayer's Reagent (mercuric potassium iodide solution) is 
prepared by dissolving 1.36 grams of corrosive mercuric chloride 
in 60 cc. of distilled water, and 5 grams of potassium iodide in 
10 cc. of water. Mix the two solutions and then add sufficient 
water to measure 100 cc. 

Millon's Reagent. — Dissolve 100 grams of mercury in 200 
grams of strong nitric acid, by the aid of heat finally, and after 
cooling dilute the solution with twice its volume of water. 

Nessler's Reagent. — Place 35 grams of potassium iodide and 
50 grams of mercuric iodide, both finely powdered, in a 500 cc. 
volumetric flask and add about 200 cc. of water: Now add to this 
mixture in the flask; with constant shaking, 250 cc. of a cooled 
20 per cent, solution of sodium hydroxide. Then make up to 
500 cc. Set aside in a warm place for several days and decant 
the clear liquid for use. 

Phospho-tungstic acid solution is prepared by adding a little 
20 per cent, phosphoric acid to an aqueous solution of sodium 
tungstate. 

Platinum chloride is used in a 5 per cent, solution. 

Sodium Hypochlorite Solution. — Prepare a solution of calcium 
hypochlorite from bleaching lime and then precipitate the 
calcium by adding an excess of sodium carbonate — allow to 
settle and use the clear supernatant liquid. 

Magnesia Mixture. — Dissolve 52.5 grams of crystallized 
magnesium sulphate and 105 grams of ammonium chloride in 
about 300 cc. of water and add 180 cc. of concentrated ammon- 
ium hydroxide. Dilute to 600 cc. Filter off turbidity which 
may develop on standing. 



INDEX 



Abrin, 323, 381 
Acetal, 58, 184 
Acetaldehyde, 55 
Acetanilide, 112, 120, 380, 392 
Acetic acid, 66 

Acetoacetic acid, formation by ami- 
no acids, 319-320 
Aceto-catechol, activity of deriva- 
tives of, 232-233 
Acetone, 62-63, 380, 387 
Acetphenetidin, 111, 120 
Acetyl atoxyl, 365 
Acetyl number, 155 
Acid number of fats, 151 
Acid taste, 208 
Acidosis, 357-359 

detection of in body, 359 
Acids, pharmacology of, 78 
Aconitine, 296 
Acridine, 132, 363 
Acrolein, 30 
Adenase, 287 
Adenine, 283-287 
Adrenaline, 245 
Adrenalone, 236 
Adsorption, 349 
Aetioporphyrin, 331 
Agar, 140 

Agglutinins, vegetable, 322 
Agmatine, 238 
Alanine, 304, 312 
Albuminoids, 300 
Albumins, 299 
Alcohol, absolute, 19 

action of, 20 

amyl, 26 

as a food, 21 

butyl, 24-25 . 

cetyl, 30 



Alcohol, dihydric, 28 

fate of in body, 22 

myricyl, 30 

pharmacology of in relation to 
chemistry, 31 

propyl, 24-25 

toxicity of various, 25 

trihydric, 29 
Alcohols, 17 

Aldehydes, 48-49 
Alkalies, 381, 403 
Alkalinity, actual and potential, 355 

of blood, 356 
Alkaloidal factors, 297 
Alkaloids, 223-298 

chemistry of, 225 

general characteristics of, 224 

isolation of, 292 

utilization by plant life, 298 
Alkanet, 334 
Alkaptonuria, 320-321 
Alkyl groups, physiological action 

of, 230 
Alkyl radicals, depressive action of, 32 
Alizarine-Bordeaux, 132 
Allantoine, 290-291 
Alloxan, 288 
Alloxantine, 288 
Aloes, 195 
Amber, 181 
Amines, 225-228 
Amines, physiological action of, 230- 

231 
Amino acids, metabolism of, 315 

occurrence in plants, 302 

occurrence in the urine, 317 

optical properties, 314 

pathology of, 319-322 

properties of, 308-309 
Ammoniac, 182 
Ammonium molybdate solution, 406 



409 



410 



INDEX 



Amygdalin, 193-198 

Analgesics, 41 

Anesthesia, stages of ether, 33-34 

theories of, 36 
Anesthesine, 267 
Anesthetics, 32 
Aniline, 110, 230, 380-387 
Aniline tests, 112 
Animal glucosides, 201 
Anisol, 90 
Annato, 334 

Anthracene derivatives, 195 
Anthracenes, 129 
Anthragallol, 132 
Anthranilic acid, taste of, 210 
Anthranol, 222 
Anthrapurpurin, 132 
Anthraquinone, 129 
Antimony, 381, 395-397, 401 
Antipyrine, 113, 117, 119, 380-381, 

392 
Apocodeine, 279 
Apomorphine, 276, 279 
Arbutin, 192 
Arecoline, 257-258 
Arginine, 234, 238, 303, 308 
Aristol, 366 
.Aromatic alcohols, 101 
Arrenhal, 366 
Arsacetin, 365 
Arsenic, 381, 395-398, 401 

compounds, 364 

fate in body, 367-368 
Arsphenamine, 366 
Asafcetida, 176, 182 
Ash, 10-11 

Aspartic acid, 306, 315 
Asp'idium, 181 
Aspidosamine, 296 
Aspidospermatine, 296 
Aspirin, 106 
Astringents, 214, 369 
Atophan, 109 
Atoxyl, 364 
Atropine, 239, 244, 251, 271-272, 

368, 380 
Attar of Roses, 169 



B 



Balsams, 180-182 

Barbituric acid, 285-286 

Barfoed's reagent, 406 

Barium, 381, 394, 399-401 

Bear fat, 145 

Beer, 20 

Bee's wax, 164 

Benedict's sugar reagent, 406 

Benzaldehyde, 100, 103, 193, 380, 
387 

Benzene, 13, 87-89 

Benzine, 13, 14 

Benzoic acid, 104, 105 

Benzyl alcohol, 101-102 

Benzyl amine, 230 

Berberine, 262 

Betaine, 234 

Bikhaconitine, 296 

Bile pigments, 333 

Bismuth, 381, 395, 398-401 

Bitter principles, 204 

Bitter taste, 208-214 

Bitters, pharmacologic classifica- 
tion of, 205 

Black pepper, 181 

Blood pressure, effect of amines on, 
231 

Boiling point, changes with mole- 
cular weight, 15 

Borneol-camphor, 177 

Brandy, 20 

Bromine compounds, 87 

Bromine test for fats, 158 

Bromopin, 86 

Brucine, 251, 257, 380 

Brucine, ethyl, 228 

Buffer value, 355 



Cacodyl oxide, 365 
Cacodylic acid, 365 
Cadaverine, 231, 234, 240-241 
Cadmium, 381, 395, 398, 401 
Caffeine, 287, 380-381, 392 



INDEX 



411 



Caffeine, action of, 2S8 

assay of, 292 

economic use of. 291 

diuretic action of, 289 

fate of, 290 

group, 2S3 

isolation of, 293 
Camphor, 178-179 
Camphor monobromata, 17S 
Camphorol, 179 
Cantharidin, 381, 392. 403-404 
Caoutchouc. 182 
Capsicum, 182 
Caramel, 334 
Carbamate, 313 

Carbamino, reaction of amino acids, 
Carbon disulphide, 380, 388 
Carbohydrate tests, 137 
Carbohydrates, 135 
Carbolic acid, distribution of in 

body, 92 
Carbonic acid, 67-68 
Carminatives, 177 
Carmine, 334 

Carnivora, poisoning of, 374 
Carvacrol, 181 
Castor oil, 149 
Castor oil group, 146 
Catechol, 93-94, 233, 235 
Celluloses, 136, 140 
Central nervous system, toxic ac- 
tion of heavy metals on, 
371 
Cerebron, 199 
Cerebronic acid, 199 
Chaulmoogra oil, 148 
Chloral, 57-61 
Chloral, fate of in body, 59 

in urine, 61 
Chloral hydrate, 380, 389 
Chloraldehyde, 57-58- 
Chlorates, 381, 403 
Chloretone, 63-64 
Chlorocodeine, 2S0 
Chloroform, 34-35, 41-42, 380 
Chlorophyll, 269, 328-335 

fate in the body, 333 



Chlorophylls and hemoglobins, re- 
lationship of, 329 

Cholesterol, 153, 166-169 

Choline, 234, 240, 242 

Chromium, 381, 399-401 

Chromoporteins, 300 

Chrysophanic acid, 131, 196, 222 

Chrysorobin, 219, 222 

Cinchona bark, 260 

Citric acid, 73-74 

Cloves, 177 

Clupanodonic acid series, 148 

Coca, 265, 267 

Cocaine, 251, 265-267, 380 

Cocoanut oil, 147 

Codeine, 239, 276, 278-279, 281, 380 

Coffee, caffein in, 286 

Colchiceine, 295-296 

Colchicine, 295-296, 380, 392 

Collidine, 250 

Colloidal copper, gold, platinum and 
silver, 372 

Colloidal metals, 372 

Colloids, 335-350 

Colloids, changes in during precipi- 
tation, 342 

Colloids, electrical condition of, 341 

Colloids, protective power of, 342 

Colormetric method, 351 

Coniferin, 200 

Coniferyl alcohol, 200 

Coniine, 239, 250-252 

Convallamarin, 197 

Copaiba, 182-183 

Copper, 177, 395, 397-399, 401 

Coriander, 177 

Corrosive salts, 369 

Cottonseed oil, 149, 177 

Cranberries, 183 

Creatine, 249 

Creatinine, 249 

Creosote, 98, 380, 390 

Cresols, 96-97 

Crocus, 334 

Croton, 322, 381 

Croton oil, 149 

Crude fiber, 140 



412 



INDEX 



Cubebs, 177, 182 . 
Cudbear, 334 
Curara, 228, 230 
Curcin, 322, 381 
Curcumin, 334 
Cyanogenetic glucosides, 198 
Cysteic acid, 320 
Cysteine, 306, 320 
Cystine, 306 
Cystinuria, 241 
Cytisine, 271, 381, 404 



Ergot, derivatives of, 245 
Ergot alkaloids, 234 
Ergotinine, 296 
Ergotoxine, 234, 245, 296 
Esbach's reagent, 406 
Eserine, 294 
Ethane, 16 
Ether, 34, 36-39 
Ethyl alcohol, 19, 380, 389 

tests for, 23-24 
Ethyl chloride, 41 
Eugenol, 200 
Europhen, 82 



Dhurrin, 198 

Diastases, 324 

Diffusion, 375 

Digallic acid, 214 

Digitalein, 198 

Digitalin, 197 

Digitalis, 197, 381, 392, 405 

Digitoxin, 197 

Disaccharides, 135 

Dithymol-di-iodide, 81-82 

Diuresis, 289 

Drug, definition of, 1 

Drugs, classification of, 2-4 

Dulcin, taste of, 210 



Ecgonine, 266 
Elaidic acid, 148 
Elaidin test for fats, 157 
Elaterin, 219, 222 
Electro-potential method, 351 
Emodin, 131, 133, 196 
Emulsoid, 338-339 
Enolforms, 116 
Enzymes, 323-328 

fate in body, 325 
Epinephrine, 231, 234-237 

stimulation of sympathetica by, 
235-236 

tests, 237 
Ergot, 231, 244-245, 320, 381, 405 



Fat, appearance after anesthesia, 
159 

butter, 147 

formation from protein, 163 

formation of from carbohy- 
drate, 162 

from carbohydrate, 161-162 

from fat, 161-162 

human, 147 

in urine, 164 

influence of diet on, 146 

wool, 165 
Fats, constants of, 152 

fate of, 160 

fate of in the body, 164 

hydrogenated, 155 

melting point of, 152 

properties of, 149-150 

rancidity of, 159 

significance of, 160 
Fatty acids, fats and oils, 144 
Fehling's solution, 138, 406 
Fermentation, 139 
Ferments, table of, 326-328 
Fixed and volatile oils, differences 

between, 174 
Flavopurpurin, 133 
Flavoring agents, 177 
Food, definition of, 1 
Formaldehyde, 50-54 
Formic acid, 65 



INDEX 



413 



Fowler's solution, 364 
Frangula, 196 
Froehde's reagent, 406 
Furfural, 137 
Fusel oil, 27 

G 

Galactose, 138 

Galactosides, 184 

Gallic acid, 95, 216 

Gallotanic acid, 214 

Gamboge, 182-183 

Gas chain method, 351-352 

Gas pressure, relation to osmotic 

pressure, 375-377 
Genito-urinary disinfectants, 177 
Gel formation, 339 
Gin, 20 
Ginger, 182 
Gliadins, 300 
Globulins, 299 
Glucose formation by amino acids, 

319-320 
Glucophore group, definition of, 211 

list of, 211-214 
Glucoproteins, 300 
Glucosides, 184-204 
action of, 202 
animal, 199 
composition of, 189 
cyanogenetic, 198 
fate of, 202 
functions of, 202 
table of, 191 
tests for, 203-204. 
Glutamic acid, 306, 316 
Glutelins, 299 
Glyceric acid, 316 
Glycerine, 29, 312 
Glycocoll, 304 
Glycol, 28-29 
Glycolaldehyde, 29 
Glycuronic acid, 176 
Glycyrrhizin, 198 
Glyoxal, 29 



Glyoxaline, 273 
Goa powder, 222 
Gold chloride, 406 
Gout, 290 

Guaiacum-wood, 182 
Guanidine derivatives, 238 
Guanine, 283-287 
Gum resins, 181-183 
Gums, 136, 142 
Gynocardin, 198 

H 

Haematin, 332 

Haematinic acid, 329 

Hsemoporphyrin, 331 

Heart, effect of alcohols on, 25 

Heavy metals, 368-372 

Helleborin, 198 

Hematic acid, 333 

Hematoporphyrin, 331 

Hemicellulose, 141 

Hemoglobins, 300, 333 

Hemotoxylin, 334 

Herbivora, poisoning of, 374 

Hetero-cyclic compounds, 134 

Hexamethylenamine, 54 

Hexone bases, 238 

Hippuric acid, 106 

Histamine, 234, 246, 322 

Histidine, 238, 245-246, 308, 322 

Histones, 300 

Homogentisic acid, 317-318, 321 

Hordenine, 237 

Hyderabad Commission, 37 

Hydrargyri iodidi, 364 

Hydrastine, 262-264, 380 

Hydrastinine, 262-264 

Hydro-cotarnine, 265 

Hydrocyanic acid, 75-77, 380 

Hydrogen, 7-8 

Hydrogen ion concentration, 352- 

354 
Hydro quinone, 93 
Hygrine, 267 
Hyoscine, 272 
Hyoscyamine, 239 



414 



INDEX 



Hypnotics, 41, 43, 45 
Hypoquebrachine, 296 
Hypoxanthine, 291 



I 



Indaconitine, 296 
Indican, 200, 334 
Indigo Blue, 201 

white, 201 
Inks, 215 
Inorganic acids, pharmacology of, 

373-4 
Indoxyl, 201, 335 
Iodine number of fats, 154-155 

solution, 407 
Iodoalbin, 84 

Iodoform, 80-81, 85-86, 380, 390 
Iodol, 82 
Indole, 202, 335 
Iodopin, 83 
Iodo-spongin, 84 

Irritant action of heavy metals, 371 
Isoamylamine, 234 
Isomerism, 24 
Isopurpuric acid, 78 



Jalap, 182 
Jalapin, 193 
Japaconitine, 296 

K 

Kerosene, 14 

Ketones, 62 

Kidney function, 127 

Kola nuts, caffeine in, 286 

Kuskhygrine, 267 

Kynurenic acid, 321 



Lactams, 310 

Lactic acid, 74-75, 315 



Lactims, 310 
Lanolin, 165, 178 
Laudanine, 279 
Lavender, 177, 334 
Lead, 381, 395, 398-401 
Lecithin, 243 
Lecithoproteins, 301 
Lemon, 177 
Leucine, 26, 302, 305 
Lignoceric acid, 199 
Ligroin, 14 

Linolic acid series,* 148 
Linseed oil group, 146 
Lipoproteins, 301 
Losophan, 83 
Lotusin, 198 
Lupine, 271 
Lupulin, 182 
Luqor arseni, 364 
Lyotrope, 340-341 
Lysine, 238, 308 

M 

Magnesia mixture, 407 

Malodorous oils, 177 

Malonic acid, 70 

Mandelic acid, 194, 271 

Maumene or sulphuric acid test, 158 

Mayer's reagent, 407 

Menthol, 179-180 

Mercaptans, 30 

Mercury, 381, 398, 401 

Mesotan, 108 

Meta-proteins, 301 

Methane, 15-16 

Methyl alcohol, 18, 380, 390 

Methylated compounds, 249 

Methylation in animal body, 249, 
270 

Meyer-Overton, Theory of anes- 
thesia, 36 

Millon's reagent, 407 

Mineral acids, 381, 401 

Monosaccharides, 135 

Moore and Roaf, Theory of anes- 
thesia, 37 



INDEX 



415 



Morphine, 239, 251, 276, 281, 381 

methyl, 228 

pharmacology of, 279 
Mucic acid, 137 
Murexide, 79 

test, 288 
Muscarine, 234, 240 

pharmacological action of, 244 
Mustard oil, 192 
Myronic acid, 192 
Myrrh, 183 



N 



Naphthalenes, 120 

Naphthols, 129 

Xarceine, 381 

Narcotine, 251, 264, 279, 380 

Neo-salvarsan, 367 

Xessler's reagent, 407 

Neurine, 240, 242 

Neutral principles, 219 

Xicotine, 239, 247, 251-254, 380 

Nicotine, ethyl, 228 

Nicotinic acid, 255-256 

Niger, 271 

Nitric acid, 401-402 

Nitrobenzene, 380, 390 

Nitrogen, 7-9 

Nitrogen bases, 223-298 

Nitrophenols, 112 

Nosophen, 83, 126 

Nova came, 267 

Nucleic acid, 29p 

Nucleo proteins, 300 



Odors, chemistry of, 207-208 

classification of, 205-207 

physics of, 207-208 
Oils, classification of, 145-146 

drying, 145 

non-drying, 145 

essential, 169 

ethereal, 169 

solubility in alcohol of, 149 



Oils, malodorous, 177 

Oleic acid series, 147 

Oleoresins, 181-182' 

Olive oil, 149 

Olive oil group, 145 

Opianic acid, 262-263 

Opium, 381 

Opsonic index, 344 

Optical activity, 71-72 

Oxalic acid, 69 

Organic acids, 64 

Ornithine, 238, 241 

Osmophore groups, 207 

Osmosis, 375 

Osmotic pressure, relation to 
boiling point, 377-8 

Osmotic pressure, relation to freez- 
ing point, 377-378 

Oxalates, 402 

Oxalic acid, 381 

Oxygen, 10 



Palm oil, 148 

Pancreatic ferments, 324 

Papaverine, 261, 282 

Paraffins, 12 

Paraldehyde, 57 

Paralytic action of alkaloids, 228 

Pectin, preparation, 144 

Pectins, 143 

Pelletierine, 270 

Pentosides, 184 

Peppermint, 177 

Peptides, 301 

Peptones, 301 

Peru, balsam of, 183 

Petrolatum, liquid, 14 

Petroleum, 13 

Petroleum ether, 14 

Pharmacology, definition of, 1 

Phenacein, 112, 121, 380, 392 

Phenanthrene, 275 

Phenetidin, 111-112 

Phenol, properties of, 91-92 

Phenols, 90, 380, 390 



416 



INDEX 



Phenols, reactions of, 99-102 
Phenolphthalein, 124 
Phenolsulphonephthalein, 127 
Phenyl-alanine, 303-307, 321 
Phloretin, 195 
Phloridzin, 189, 194 
Phloroglucinol, 95 

taste of, 210 
Phosphine, 363-364 
Phosphoproteins, 300 
Phosphorus, 361-363 

isolation of, 380-387 
Phosphotungstic acid solution, 407 
Phrenosin, 199 
Phthalic acid, 125 
Phthalimide, 210 
Physostigmine, 294-295, 380 
Phytosterol, 153 
Phytotoxins, 322-323 
Picolinic acid, 255 
Picramic acid, 78, 99 
Picric acid, 98-99, 380, 392 
Picrotoxin, 219-222, 380, 392 
Pilocarpine, 244, 274-275, 380-381 
Pilocarpine, action of, 274 
Piperazine, 310 
Piperic acid, 248 
Piperidine, 135, 226, 242, 247-248, 

250, 268 
Pituitarine, 246 
Plant bases, 223-298 
Platinum chloride, 407 
Podophyllum, 182 
Poison, definition of, 1 
Poisons, isolation of, 379-389 
Poisonous proteins, 322 
Polysaccharides, 135 
Potassium cyanide, 387 
Precipitation of colloids, 369-371 
Pressor substances, 231 
Prolamines, 300 
Proline, 303, 307-308 
Protamines, 300 
Proteans, 301 
Proteins, 298-304 

coagulated, 301 

color reactions of, 303 



Proteins, comparison of animal and 
vegetable, 302 

composition of, 303 

conjugated, 300 

derived, 301 

English classification, 302 

hydrolytic products of, 304 

precipitation reactions of, 304 
Proteoses, 301 
Proximate principles, 2 
Prulaurasin, 198 
Ptomaines, 239, 381 
Purin metabolism, 290 
Purine, 283-287 
Purpuric acid, 288 
Purpuroxanthin, 133 
Putrescine, 234, 240 
Pyramidon, 118-119, 380 
Pyrazolon, 115 
Pyridine, 134 ' 

alkaloids, 247-249, 251 
Pyrocatechol, 94 
Pyrocatechol, fast* of, 210 
Pyrogallic acid, 9o 
Pyrogallol, 95, 216 

taste of, 210 
Pyrrol, 250, 269, 330 
Pyrrolidine alkaloids, 267 
Pyrollidine, 268-269 
Pyruvic acid, 312 



Q 



Quaternary ammonium bases, 228- 

231 
Quebrachamine, 296 
Quebrachine, 296 
Quebractio alkaloids, 296 
Quinine, 251, 259-261, 380 
Quinol, 93 
Quinoline, 258 

alkaloids, 259 
Quinones, 93, 131 

R 

Rattlesnake fat, 146 

Reaction of living matter, 350-361 



INDEX 



417 



Reichert Meissel number, 156 
Regulating mechanism of blood 

reaction, 354 
Resins, 181-182 
Resorcinol, 42, 92-93 

taste of, 210 
Rhubarb, 196 
Ricin, 322, 381 
Ricinoleic-oleic series, 148 
Robin, 322, 381 
Rose, 177 
Rosolic acid, 42 
Rum, 20 



Sabromine, 86 
Saccharin, 122 

taste of, 210 

taste of derivatives of, 210 
Salicylic acid, 106, 380, 392 

tests, 121 
Saligenin, 103, 194 
Saline taste, 208 
Salol, 101, 107 
Salol principle, 101 
Salt action, 374 

pharmacology of, 379 
Salts in body, 378 
Salvarsan or "606," 366-367 
Sambunigrin, 198 
Sandalwood, 177 
Santonic acid, 219 
Santonin, 219-220, 381, 404 
Saponification, 177 

number of fats, 152 
Saponins, 196, 381 
Scammonium, 193 
Scammony, 182-183 
Scillin, 198 
Sclero-proteins, 302 
Scopolamine, 272, 380 
Scopoline, 272 
Senna, 196 
Serine, 306 
Silver, 400-1 
27 



Sinapic acid, 243 

Sinapin, 192, 243 

Sinigrin, 192 

Smell, pharmacology of, 205 

Soap, cleansing action of, 150-152 

Soaps, medicated, 150 

Sodium hypochlorite solution, 407 

Solanine, 199, 381 

Sorensen titration of amino acids, 

311 
Specific dynamic action, 316 
Spermaceti, 30 
Sphingosin, 199 
Stachydrine, 244, 268 
Starches, 136, 138 
Stearic acid, 151 
Stearoptenes, 178 
Sterols, 166 
Storax, balsam of, 183 
Strophanthin, 195 
Strychnine, 239, 251, 256-257, 380 

methyl, 228 
Stryolene derivatives, 194 
Styptics, 369 
Succinic, acid, 
Sugars, 136 

tests for, 139 

uses, 139 
Sulphonal, 46, 381, 404 
Sulphones, 45 
Sulphuric acid, 401 
Surface tension, 343-348 
Suspensoids, 338-339 
Sweet taste, 208-314 
Sympathetic nerves, stimulation of, 

235 
Sympathomimetic action, 233 



Tannic acid, 96, 214-217 

Tannins, 215 

Tar camphor, 128 

Tartaric acid, 71 

Taste, 208-214 

pharmacology of, 205 
theory of, 211^214 



418 



^v i > 2 v 



INDEX 






Taurine, 320 

Tea, determination of tannins in, 
218 
caffein in, 286 
Tellurium, 249 
Tension of carbon dioxide in respired 

air, 360-361 
Terpenes, 170-173 
Tetranol 

Thalleioquine test, 261 
Thebaine, 276, 279, 282 
Theobromine, 283-287 
Theophylline, 283-287 
Thymol iodide, 122-123 
Thymolis iodidum, 180 
Thyreoglobulin, 84 
Tiglic acid, 148 
Tin, 381, 397, 401 
Tolu, balsam of, 183 
Toluene, 101-102 
Toxicology, 379 
Trional, 46, 381, 404 
Tropane, 268, 270 
Tropic acid, 271 
Tropine, 271 
Tryptophane, 303, 307 
Tyrosine, 231, 307, 317, 321 
Tryptophane acid, 321 
Tyramine, 231 
Turpentine, 177 



U 



Ulcers, 371 

Unsaponifiable residue of fats, 153 
Unsaturated compounds, physiolo- 
gical activity of, 148. 
Urea, 68-69, 313 
Urethane, 43 



Uric acid, 283-287, 291 
Urinary changes in acidosis, 360 



Valerian, 177 

Valine, 305 

Vanillin, 200 

Vaso-motor reversal, 245 

Verworn's Theory of anesthesia, 37 

Veratrine, 239 272, 294, 380, 392 

Veronal, 380, 392 

Vicianin, 198 

Vioform, 83 

Viscosity, 345-348 

Vital activity, 1 

Vitamine, 164 

Volatile oils, action of, 175 

Volatile oils, classification of, 170 

W 

Walden's inversion, 314 
Wax, Japan, 165 
Waxes, 165 
Whiskey, 20 
White arsenic, 364 
Wine, 20 

X 

Xanthine, 283-287, 291 

Y 

Yohimbine, 296 
Yohimbinine, 296 ' 



Zinc, 399, 401 



LIBRARY OF CONGRESS 



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